@article {2024, title = {A Perspective on the Prospective Use of AI in Protein Structure Prediction}, journal = {J Chem Inf Model}, volume = {64}, year = {2024}, month = {Jan}, pages = {26{\textendash}41}, author = {Versini, R. and Sritharan, S. and Aykac Fas, B. and Tubiana, T. and Aimeur, S. Z. and Henri, J. and Erard, M. and N{\"u}sse, O. and Andreani, J. and Baaden, M. and Fuchs, P. and Galochkina, T. and Chatzigoulas, A. and Cournia, Z. and Santuz, H. and S Sacquin-Mora and Taly, A.} } @article {2023|2163, title = {Best Practices of Using AI-Based Models in Crystallography and Their Impact in Structural Biology}, journal = {J Chem Inf Model}, year = {2023}, month = {Jun}, author = {Graille, M and S Sacquin-Mora and Antoine Taly} } @article {2023|2164, title = {Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 May 05}, pages = {2594}, abstract = {

Brown adipose tissue expresses uncoupling protein 1 (UCP1), which dissipates energy as heat, making it a target for treating metabolic disorders. Here, we investigate how purine nucleotides inhibit respiration uncoupling by UCP1. Our molecular simulations predict that GDP and GTP bind UCP1 in the common substrate binding site in an upright orientation, where the base moiety interacts with conserved residues R92 and E191. We identify a triplet of uncharged residues, F88/I187/W281, forming hydrophobic contacts with nucleotides. In yeast spheroplast respiration assays, both I187A and W281A mutants increase the fatty acid-induced uncoupling activity of UCP1 and partially suppress the inhibition of UCP1 activity by nucleotides. The F88A/I187A/W281A triple mutant is overactivated by fatty acids even at high concentrations of purine nucleotides. In simulations, E191 and W281 interact with purine but not pyrimidine bases. These results provide a molecular understanding of the selective inhibition of UCP1 by purine nucleotides.

}, keywords = {Adipose Tissue, Brown, Fatty Acids, Ion Channels, Membrane Proteins, Mitochondrial Proteins, Purine Nucleotides, Saccharomyces cerevisiae, Uncoupling Protein 1}, issn = {2041-1723}, doi = {10.1038/s41467-023-38219-9}, author = {Gagelin, Antoine and Largeau, Corentin and Masscheleyn, Sandrine and Piel, Mathilde S and Calder{\'o}n-Mora, Daniel and Bouillaud, Fr{\'e}d{\'e}ric and J{\'e}r{\^o}me H{\'e}nin and Miroux, Bruno} } @article {2022|2156, title = {Building Biological Relevance Into Integrative Modelling of Macromolecular Assemblies}, journal = {Frontiers in Molecular Biosciences}, volume = {9}, year = {2022}, pages = {826136}, abstract = {

Recent advances in structural biophysics and integrative modelling methods now allow us to decipher the structures of large macromolecular assemblies. Understanding the dynamics and mechanisms involved in their biological function requires rigorous integration of all available data. We have developed a complete modelling pipeline that includes analyses to extract biologically significant information by consistently combining automated and interactive human-guided steps. We illustrate this idea with two examples. First, we describe the ryanodine receptor, an ion channel that controls ion flux across the cell membrane through transitions between open and closed states. The conformational changes associated with the transitions are small compared to the considerable system size of the receptor; it is challenging to consistently track these states with the available cryo-EM structures. The second example involves homologous recombination, in which long filaments of a recombinase protein and DNA catalyse the exchange of homologous DNA strands to reliably repair DNA double-strand breaks. The nucleoprotein filament reaction intermediates in this process are short-lived and heterogeneous, making their structures particularly elusive. The pipeline we describe, which incorporates experimental and theoretical knowledge combined with state-of-the-art interactive and immersive modelling tools, can help overcome these challenges. In both examples, we point to new insights into biological processes that arise from such interdisciplinary approaches.

}, issn = {2296-889X}, doi = {10.3389/fmolb.2022.826136}, url = {https://www.frontiersin.org/article/10.3389/fmolb.2022.826136}, author = {Molza, Anne-Elisabeth and Westermaier, Yvonne and Moutte, Magali and Ducrot, Pierre and Danilowicz, Claudia and Godoy-Carter, Veronica and Prentiss, Mara and Robert, Charles H. and Marc Baaden and Pr{\'e}vost, Chantal} } @article {2021|2154, title = {Influences of ssDNA-RecA Filament Length on the Fidelity of Homologous Recombination}, journal = {Journal of Molecular Biology}, volume = {433}, year = {2021}, pages = {167143}, abstract = {

Chromosomal double-strand breaks can be accurately repaired by homologous recombination, but genomic rearrangement can result if the repair joins different copies of a repeated sequence. Rearrangement can be advantageous or fatal. During repair, a broken double-stranded DNA (dsDNA) is digested by the RecBCD complex from the 5 {\"A} end, leaving a sequence gap that separates two 3{\"A} single-stranded DNA (ssDNA) tails. RecA binds to the 3 {\"A} tails forming helical nucleoprotein filaments.A three-strand intermediate is formed when a RecA-bound ssDNA with L nucleotides invades a homologous region of dsDNA and forms a heteroduplex product with a length \≤ L bp. The homology dependent stability of the heteroduplex determines how rapidly and accurately homologous recombination repairs double-strand breaks. If the heteroduplex is sufficiently sequence matched, repair progresses to irreversible DNA synthesis. Otherwise, the heteroduplex should rapidly reverse. In this work, we present in vitro measurements of the L dependent stability of heteroduplex products formed by filaments with 90 \≤ L \≤ 420 nt, which is within the range observed in vivo. We find that without ATP hydrolysis, products are irreversible when L \> 50 nt. In contrast, with ATP hydrolysis when L \< 160 nt, products reverse in \< 30 seconds; however, with ATP hydrolysis when L \>= 320 nt, some products reverse in \< 30 seconds, while others last thousands of seconds. We consider why these two different filament length regimes show such distinct behaviors. We propose that the experimental results combined with theoretical insights suggest that filaments with 250 \≤ L \≤ 8500 nt optimize DSB repair.

}, keywords = {biased random walk, D-loop turnover, Double-strand break repair, genomic rearrangement, multiple reversible intermediates}, issn = {0022-2836}, doi = {https://doi.org/10.1016/j.jmb.2021.167143}, url = {https://www.sciencedirect.com/science/article/pii/S0022283621003727}, author = {Claudia Danilowicz and Evan Vietorisz and Veronica Godoy-Carter and Chantal Pr{\'e}vost and Mara Prentiss} } @article {2020|2075, title = {Characterization of β-turns by electronic circular dichroism spectroscopy: a coupled molecular dynamics and time-dependent density functional theory computational study.}, journal = {Phys Chem Chem Phys}, volume = {22}, year = {2020}, month = {2020 Jan 21}, pages = {1611-1623}, abstract = {

Electronic circular dichroism is one of the most used spectroscopic techniques for peptide and protein structural characterization. However, while valuable experimental spectra exist for α-helix, β-sheet and random coil secondary structures, previous studies showed important discrepancies for β-turns, limiting their use as a reference for structural studies. In this paper, we simulated circular dichroism spectra for the best-characterized β-turns in peptides, namely types I, II, I\&$\#$39; and II\&$\#$39;. In particular, by combining classical molecular dynamics simulations and state-of-the-art quantum time-dependent density functional theory (with the polarizable embedding multiscale model) computations, two common electronic circular dichroism patterns were found for couples of β-turn types (namely, type I/type II\&$\#$39; and type II/type I\&$\#$39;), at first for a minimal di-peptide model (Ace-Ala-Ala-NHMe), but also for all sequences tested with non-aromatic residues in the central positions. On the other hand, as expected, aromatic substitution causes important perturbations to the previously found ECD patterns. Finally, by applying suitable approximations, these patterns were subsequently rationalized based on the exciton chirality rule. All these results provide useful predictions and pave the way for a possible experimental characterization of β-turns based on circular dichroism spectroscopy.

}, keywords = {Circular Dichroism, Computational Chemistry, Computer Simulation, Molecular Dynamics Simulation, Protein Conformation, beta-Strand, Protein Structure, Tertiary}, issn = {1463-9084}, doi = {10.1039/c9cp05776e}, author = {Migliore, Mattia and Bonvicini, Andrea and Tognetti, Vincent and Guilhaudis, Laure and Marc Baaden and Oulyadi, Hassan and Joubert, Laurent and S{\'e}galas-Milazzo, Isabelle} } @article {2020|2130, title = {Direct Homologous dsDNA-dsDNA Pairing: How, Where, and Why?}, journal = {J Mol Biol}, volume = {432}, year = {2020}, month = {2020 Feb 07}, pages = {737-744}, abstract = {

The ability of homologous chromosomes (or selected chromosomal loci) to pair specifically in the apparent absence of DNA breakage and recombination represents a prominent feature of eukaryotic biology. The mechanism of homology recognition at the basis of such recombination-independent pairing has remained elusive. A number of studies have supported the idea that sequence homology can be sensed between intact DNA double helices in vivo. In particular, recent analyses of the two silencing phenomena in fungi, known as \"repeat-induced point mutation\" (RIP) and \"meiotic silencing by unpaired DNA\" (MSUD), have provided genetic evidence for the existence of the direct homologous dsDNA-dsDNA pairing. Both RIP and MSUD likely rely on the same search strategy, by which dsDNA segments are matched as arrays of interspersed base-pair triplets. This process is general and very efficient, yet it proceeds normally without the RecA/Rad51/Dmc1 proteins. Further studies of RIP and MSUD may yield surprising insights into the function of DNA in the cell.

}, issn = {1089-8638}, doi = {10.1016/j.jmb.2019.11.005}, author = {Mazur, Alexey K and Nguyen, Tinh-Suong and Gladyshev, Eugene} } @article {2020|2077, title = {Visualizing biomolecular electrostatics in virtual reality with UnityMol-APBS.}, journal = {Protein Sci}, volume = {29}, year = {2020}, month = {2020 Jan}, pages = {237-246}, abstract = {

Virtual reality is a powerful tool with the ability to immerse a user within a completely external environment. This immersion is particularly useful when visualizing and analyzing interactions between small organic molecules, molecular inorganic complexes, and biomolecular systems such as redox proteins and enzymes. A common tool used in the biomedical community to analyze such interactions is the Adaptive Poisson-Boltzmann Solver (APBS) software, which was developed to solve the equations of continuum electrostatics for large biomolecular assemblages. Numerous applications exist for using APBS in the biomedical community including analysis of protein ligand interactions and APBS has enjoyed widespread adoption throughout the biomedical community. Currently, typical use of the full APBS toolset is completed via the command line followed by visualization using a variety of two-dimensional external molecular visualization software. This process has inherent limitations: visualization of three-dimensional objects using a two-dimensional interface masks important information within the depth component. Herein, we have developed a single application, UnityMol-APBS, that provides a dual experience where users can utilize the full range of the APBS toolset, without the use of a command line interface, by use of a simple graphical user interface (GUI) for either a standard desktop or immersive virtual reality experience.

}, issn = {1469-896X}, doi = {10.1002/pro.3773}, author = {Laureanti, Joseph and Brandi, Juan and Offor, Elvis and Engel, David and Rallo, Robert and Ginovska, Bojana and Martinez, Xavier and Marc Baaden and Baker, Nathan A} } @article {2019|2076, title = {Glutathionylation primes soluble glyceraldehyde-3-phosphate dehydrogenase for late collapse into insoluble aggregates.}, journal = {Proc Natl Acad Sci U S A}, volume = {116}, year = {2019}, month = {2019 12 17}, pages = {26057-26065}, abstract = {

Protein aggregation is a complex physiological process, primarily determined by stress-related factors revealing the hidden aggregation propensity of proteins that otherwise are fully soluble. Here we report a mechanism by which glycolytic glyceraldehyde-3-phosphate dehydrogenase of (AtGAPC1) is primed to form insoluble aggregates by the glutathionylation of its catalytic cysteine (Cys149). Following a lag phase, glutathionylated AtGAPC1 initiates a self-aggregation process resulting in the formation of branched chains of globular particles made of partially misfolded and totally inactive proteins. GSH molecules within AtGAPC1 active sites are suggested to provide the initial destabilizing signal. The following removal of glutathione by the formation of an intramolecular disulfide bond between Cys149 and Cys153 reinforces the aggregation process. Physiological reductases, thioredoxins and glutaredoxins, could not dissolve AtGAPC1 aggregates but could efficiently contrast their growth. Besides acting as a protective mechanism against overoxidation, S-glutathionylation of AtGAPC1 triggers an unexpected aggregation pathway with completely different and still unexplored physiological implications.

}, issn = {1091-6490}, doi = {10.1073/pnas.1914484116}, author = {Zaffagnini, Mirko and Marchand, Christophe H and Malferrari, Marco and Murail, Samuel and Bonacchi, Sara and Genovese, Damiano and Montalti, Marco and Venturoli, Giovanni and Falini, Giuseppe and Marc Baaden and Lemaire, St{\'e}phane D and Fermani, Simona and Trost, Paolo} } @article {2019|2080, title = {Highlights from the Faraday Discussion on Artificial Water Channels, Glasgow, UK.}, journal = {Chem Commun (Camb)}, volume = {55}, year = {2019}, month = {2019 Apr 07}, pages = {3853-3858}, issn = {1364-548X}, doi = {10.1039/c9cc90112d}, author = {Barboiu, Mihail and Kumar, Manish and Marc Baaden and Gale, Philip A and Hinds, Bruce J} } @article {2019|2067, title = {An inter-dimer allosteric switch controls NMDA receptor activity}, journal = {The EMBO journal}, volume = {38}, year = {2019}, author = {Esmenjaud, Jean-Baptiste and Stroebel, David and Chan, Kelvin and Grand, Teddy and David, M{\'e}lissa and Wollmuth, Lonnie P and Antoine Taly and Paoletti, Pierre} } @article {2019|2071, title = {Involvement of the GABAA receptor α subunit in the mode of action of etifoxine}, journal = {Pharmacological research}, volume = {145}, year = {2019}, pages = {104250}, author = {Mattei, C{\'e}sar and Antoine Taly and Soualah, Zineb and Saulais, Oph{\'e}lie and Henrion, Daniel and Gu{\'e}rineau, Nathalie C and Verleye, Marc and Legros, Christian} } @article {2019|2062, title = {The positioning of Chi sites allows the RecBCD pathway to suppress some genomic rearrangements}, journal = {Nucleic Acids Res}, volume = {47}, year = {2019}, month = {02}, pages = {1836-1846}, abstract = {

Bacterial recombinational repair of double-strand breaks often begins with creation of initiating 3\&$\#$39; single-stranded DNA (ssDNA) tails on each side of a double-strand break (DSB). Importantly, if the RecBCD pathway is followed, RecBCD creates a gap between the sequences at 3\&$\#$39; ends of the initiating strands. The gap flanks the DSB and extends at least to the nearest Chi site on each strand. Once the initiating strands form ssDNA-RecA filaments, each ssDNA-RecA filament searches for homologous double-stranded DNA (dsDNA) to use as a template for the DNA synthesis needed to fill the gap created by RecBCD. Our experimental results show that the DNA synthesis requires formation of a heteroduplex dsDNA that pairs \>20 contiguous bases in the initiating strand with sequence matched bases in a strand from the original dsDNA. To trigger synthesis, the heteroduplex must be near the 3\&$\#$39; end of the initiating strand. Those experimentally determined requirements for synthesis combined with the Chi site dependence of the function of RecBCD and the distribution of Chi sites in bacterial genomes could allow the RecBCD pathway to avoid some genomic rearrangements arising from directly induced DSBs; however, the same three factors could promote other rearrangements.

}, doi = {10.1093/nar/gky1252}, author = {Li, Chastity and Danilowicz, Claudia and Tashjian, Tommy F and Godoy, Veronica G and Chantal Pr{\'e}vost and Prentiss, Mara} } @article {2019|2063, title = {Residues in the fingers domain of the translesion DNA polymerase DinB enable its unique participation in error-prone double-strand break repair}, journal = {J Biol Chem}, volume = {294}, year = {2019}, month = {May}, pages = {7588-7600}, abstract = {

The evolutionarily conserved Escherichia coli translesion DNA polymerase IV (DinB) is one of three enzymes that can bypass potentially deadly DNA lesions on the template strand during DNA replication. Remarkably, however, DinB is the only known translesion DNA polymerase active in RecA-mediated strand exchange during error-prone double-strand break repair. In this process, a single-stranded DNA (ssDNA)-RecA nucleoprotein filament invades homologous dsDNA, pairing the ssDNA with the complementary strand in the dsDNA. When exchange reaches the 3\&$\#$39; end of the ssDNA, a DNA polymerase can add nucleotides onto the end, using one strand of dsDNA as a template and displacing the other. It is unknown what makes DinB uniquely capable of participating in this reaction. To explore this topic, we performed molecular modeling of DinB\&$\#$39;s interactions with the RecA filament during strand exchange, identifying key contacts made with residues in the DinB fingers domain. These residues are highly conserved in DinB, but not in other translesion DNA polymerases. Using a novel FRET-based assay, we found that DinB variants with mutations in these conserved residues are less effective at stabilizing RecA-mediated strand exchange than native DinB. Furthermore, these variants are specifically deficient in strand displacement in the absence of RecA filament. We propose that the amino acid patch of highly conserved residues in DinB-like proteins provides a mechanistic explanation for DinB\&$\#$39;s function in strand exchange and improves our understanding of recombination by providing evidence that RecA plays a role in facilitating DinB\&$\#$39;s activity during strand exchange.

}, keywords = {DinB, DNA damage, DNA polymerase, DNA polymerase IV, DNA repair, DNA synthesis, homologous recombination, RecA}, doi = {10.1074/jbc.RA118.006233}, author = {Tashjian, Tommy F and Danilowicz, Claudia and Molza, Anne-Elizabeth and Nguyen, Brian H and Chantal Pr{\'e}vost and Prentiss, Mara and Godoy, Veronica G} } @article {2019|2064, title = {Slow extension of the invading DNA strand in a D-loop formed by RecA-mediated homologous recombination may enhance recognition of DNA homology}, journal = {J Biol Chem}, volume = {294}, year = {2019}, month = {May}, pages = {8606-8616}, abstract = {

DNA recombination resulting from RecA-mediated strand exchange aided by RecBCD proteins often enables accurate repair of DNA double-strand breaks. However, the process of recombinational repair between short DNA regions of accidental similarity can lead to fatal genomic rearrangements. Previous studies have probed how effectively RecA discriminates against interactions involving a short similar sequence that is embedded in otherwise dissimilar sequences but have not yielded fully conclusive results. Here, we present results of in vitro experiments with fluorescent probes strategically located on the interacting DNA fragments used for recombination. Our findings suggest that DNA synthesis increases the stability of the recombination products. Fluorescence measurements can also probe the homology dependence of the extension of invading DNA strands in D-loops formed by RecA-mediated strand exchange. We examined the slow extension of the invading strand in a D-loop by DNA polymerase (Pol) IV and the more rapid extension by DNA polymerase LF-Bsu We found that when DNA Pol IV extends the invading strand in a D-loop formed by RecA-mediated strand exchange, the extension afforded by 82 bp of homology is significantly longer than the extension on 50 bp of homology. In contrast, the extension of the invading strand in D-loops by DNA LF-Bsu Pol is similar for intermediates with \≥50 bp of homology. These results suggest that fatal genomic rearrangements due to the recombination of small regions of accidental homology may be reduced if RecA-mediated strand exchange is immediately followed by DNA synthesis by a slow polymerase.

}, keywords = {cooperativity, DNA damage, DNA polymerase, DNA recombination, double-strand break (DSB), fluorescence resonance energy transfer (FRET), heteroduplex formation, molecular dynamics, RecA, strand displacement synthesis}, doi = {10.1074/jbc.RA119.007554}, author = {Lu, Daniel and Danilowicz, Claudia and Tashjian, Tommy F and Chantal Pr{\'e}vost and Godoy, Veronica G and Prentiss, Mara} } @article {2019|2119, title = {Stability Effect of Quinary Interactions Reversed by Single Point Mutations}, journal = {Journal of the American Chemical Society}, volume = {141}, year = {2019}, pages = {4660-4669}, doi = {10.1021/jacs.8b13025}, url = {https://doi.org/10.1021/jacs.8b13025}, author = {Gnutt, David and Timr, Stepan and Ahlers, Jonas and K{\"o}nig, Benedikt and Manderfeld, Emily and Heyden, Matthias and Sterpone, Fabio and Ebbinghaus, Simon} } @inbook {2018|2085, title = {Applications to water transport systems: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {389-414}, issn = {1364-5498}, doi = {10.1039/c8fd90022a}, author = {Marc Baaden and Barboiu, Mihail and Borthakur, Manash Pratim and Chen, Chun-Long and Coalson, Rob and Davis, Jeffery and Freger, Viatcheslav and Gong, Bing and H{\'e}lix-Nielsen, Claus and Hickey, Robert and Hinds, Bruce and Hirunpinyopas, Wisit and Horner, Andreas and Hou, Jun-Li and Hummer, Gerhard and Iamprasertkun, Pawin and Kazushi, Kinbara and Kumar, Manish and Legrand, Yves-Marie and Lokesh, Mahesh and Mi, Baoxia and Mitra, Sushanta and Murail, Samuel and Noy, Aleksandr and Nunes, Suzana and Pohl, Peter and Song, Qilei and Song, Woochul and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish} } @inbook {2018|2082, title = {Biomimetic water channels: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {205-229}, issn = {1364-5498}, doi = {10.1039/c8fd90020e}, author = {Marc Baaden and Barboiu, Mihail and Bill, Roslyn M and Chen, Chun-Long and Davis, Jeffery and Di Vincenzo, Maria and Freger, Viatcheslav and Fr{\"o}ba, Michael and Gale, Philip A and Gong, Bing and H{\'e}lix-Nielsen, Claus and Hickey, Robert and Hinds, Bruce and Hou, Jun-Li and Hummer, Gerhard and Kumar, Manish and Legrand, Yves-Marie and Lokesh, Mahesh and Mi, Baoxia and Murail, Samuel and Pohl, Peter and Sansom, Mark and Song, Qilei and Song, Woochul and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish and V{\"o}gele, Martin} } @article {2018|2137, title = {Conformational entropy of a single peptide controlled under force governs protease recognition and catalysis}, journal = {Proc Natl Acad Sci U S A}, volume = {115}, year = {2018}, month = {11}, pages = {11525-11530}, abstract = {

An immense repertoire of protein chemical modifications catalyzed by enzymes is available as proteomics data. Quantifying the impact of the conformational dynamics of the modified peptide remains challenging to understand the decisive kinetics and amino acid sequence specificity of these enzymatic reactions in vivo, because the target peptide must be disordered to accommodate the specific enzyme-binding site. Here, we were able to control the conformation of a single-molecule peptide chain by applying mechanical force to activate and monitor its specific cleavage by a model protease. We found that the conformational entropy impacts the reaction in two distinct ways. First, the flexibility and accessibility of the substrate peptide greatly increase upon mechanical unfolding. Second, the conformational sampling of the disordered peptide drives the specific recognition, revealing force-dependent reaction kinetics. These results support a mechanism of peptide recognition based on conformational selection from an ensemble that we were able to quantify with a torsional free-energy model. Our approach can be used to predict how entropy affects site-specific modifications of proteins and prompts conformational and mechanical selectivity.

}, keywords = {enzymology, mechanics, proteases, single molecule, torsional free energy}, doi = {10.1073/pnas.1803872115}, author = {Guerin, Marcelo E and Guillaume Stirnemann and Giganti, David} } @article {2018|2134, title = {DNA Binding Induces a Nanomechanical Switch in the RRM1 Domain of TDP-43}, journal = {J Phys Chem Lett}, volume = {9}, year = {2018}, month = {Jul}, pages = {3800-3807}, abstract = {

Understanding the molecular mechanisms governing protein-nucleic acid interactions is fundamental to many nuclear processes. However, how nucleic acid binding affects the conformation and dynamics of the substrate protein remains poorly understood. Here we use a combination of single molecule force spectroscopy AFM and biochemical assays to show that the binding of TG-rich ssDNA triggers a mechanical switch in the RRM1 domain of TDP-43, toggling between an entropic spring devoid of mechanical stability and a shock absorber bound-form that resists unfolding forces of \∼40 pN. The fraction of mechanically resistant proteins correlates with an increasing length of the TG n oligonucleotide, demonstrating that protein mechanical stability is a direct reporter of nucleic acid binding. Steered molecular dynamics simulations on related RNA oligonucleotides reveal that the increased mechanical stability fingerprinting the holo-form is likely to stem from a unique scenario whereby the nucleic acid acts as a \"mechanical staple\" that protects RRM1 from mechanical unfolding. Our approach highlights nucleic acid binding as an effective strategy to control protein nanomechanics.

}, doi = {10.1021/acs.jpclett.8b01494}, author = {Wang, Yong Jian and Rico-Lastres, Palma and Lezamiz, Ainhoa and Mora, Marc and Solsona, Carles and Guillaume Stirnemann and Garcia-Manyes, Sergi} } @article {2018|2093, title = {Dystrophin{\textquoteright}s central domain forms a complex filament that becomes disorganized by in-frame deletions.}, journal = {J Biol Chem}, volume = {293}, year = {2018}, month = {2018 05 04}, pages = {6637-6646}, abstract = {

Dystrophin, encoded by the gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin\&$\#$39;s central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45-47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD.

}, keywords = {Binding Sites, Dystrophin, Exons, Gene Deletion, Humans, Molecular Docking Simulation, Muscular Dystrophy, Duchenne, Nitric Oxide Synthase Type I, Protein Domains, Reading Frames, Scattering, Small Angle, Solutions, X-Ray Diffraction}, issn = {1083-351X}, doi = {10.1074/jbc.M117.809798}, author = {Delalande, Olivier and Molza, Anne-Elisabeth and Dos Santos Morais, Raphael and Ch{\'e}ron, Ang{\'e}lique and Pollet, {\'E}meline and Raguenes-Nicol, C{\'e}line and Tascon, Christophe and Giudice, Emmanuel and Guilbaud, Marine and Nicolas, Aur{\'e}lie and Bondon, Arnaud and Leturcq, France and Nicolas F{\'e}rey and Marc Baaden and Perez, Javier and Roblin, Pierre and Pi{\'e}tri-Rouxel, France and Hubert, Jean-Fran{\c c}ois and Czjzek, Mirjam and Le Rumeur, Elisabeth} } @article {2018|2132, title = {The force-dependent mechanism of DnaK-mediated mechanical folding}, journal = {Sci Adv}, volume = {4}, year = {2018}, month = {Feb}, pages = {eaaq0243}, abstract = {

It is well established that chaperones modulate the protein folding free-energy landscape. However, the molecular determinants underlying chaperone-mediated mechanical folding remain largely elusive, primarily because the force-extended unfolded conformation fundamentally differs from that characterized in biochemistry experiments. We use single-molecule force-clamp spectroscopy, combined with molecular dynamics simulations, to study the effect that the Hsp70 system has on the mechanical folding of three mechanically stiff model proteins. Our results demonstrate that, when working independently, DnaJ (Hsp40) and DnaK (Hsp70) work as holdases, blocking refolding by binding to distinct substrate conformations. Whereas DnaK binds to molten globule-like forms, DnaJ recognizes a cryptic sequence in the extended state in an unanticipated force-dependent manner. By contrast, the synergetic coupling of the Hsp70 system exhibits a marked foldase behavior. Our results offer unprecedented molecular and kinetic insights into the mechanisms by which mechanical force finely regulates chaperone binding, directly affecting protein elasticity.

}, doi = {10.1126/sciadv.aaq0243}, author = {Perales-Calvo, Judit and Giganti, David and Guillaume Stirnemann and Garcia-Manyes, Sergi} } @article {2018|2136, title = {Forcing the reversibility of a mechanochemical reaction}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {08}, pages = {3155}, abstract = {

Mechanical force modifies the free-energy surface of chemical reactions, often enabling thermodynamically unfavoured reaction pathways. Most of our molecular understanding of force-induced reactivity is restricted to the irreversible homolytic scission of covalent bonds and ring-opening in polymer mechanophores. Whether mechanical force can by-pass thermodynamically locked reactivity in heterolytic bimolecular reactions and how this impacts the reaction reversibility remains poorly understood. Using single-molecule force-clamp spectroscopy, here we show that mechanical force promotes the thermodynamically disfavored SN2 cleavage of an individual protein disulfide bond by poor nucleophilic organic thiols. Upon force removal, the transition from the resulting high-energy unstable mixed disulfide product back to the initial, low-energy disulfide bond reactant becomes suddenly spontaneous, rendering the reaction fully reversible. By rationally varying the nucleophilicity of a series of small thiols, we demonstrate how force-regulated chemical kinetics can be finely coupled with thermodynamics to predict and modulate the reversibility of bimolecular mechanochemical reactions.

}, doi = {10.1038/s41467-018-05115-6}, author = {Beedle, Amy E M and Mora, Marc and Davis, Colin T and Snijders, Ambrosius P and Guillaume Stirnemann and Garcia-Manyes, Sergi} } @article {2018|2044, title = {Meet-U: Educating through research immersion}, journal = {PLOS Computational Biology}, volume = {14}, year = {2018}, month = {03}, pages = {1-10}, abstract = {

We present a new educational initiative called Meet-U that aims to train students for collaborative work in computational biology and to bridge the gap between education and research. Meet-U mimics the setup of collaborative research projects and takes advantage of the most popular tools for collaborative work and of cloud computing. Students are grouped in teams of 4\–5 people and have to realize a project from A to Z that answers a challenging question in biology. Meet-U promotes \"coopetition,\" as the students collaborate within and across the teams and are also in competition with each other to develop the best final product. Meet-U fosters interactions between different actors of education and research through the organization of a meeting day, open to everyone, where the students present their work to a jury of researchers and jury members give research seminars. This very unique combination of education and research is strongly motivating for the students and provides a formidable opportunity for a scientific community to unite and increase its visibility. We report on our experience with Meet-U in two French universities with master\’s students in bioinformatics and modeling, with protein\–protein docking as the subject of the course. Meet-U is easy to implement and can be straightforwardly transferred to other fields and/or universities. All the information and data are available at www.meet-u.org.

}, doi = {10.1371/journal.pcbi.1005992}, url = {https://doi.org/10.1371/journal.pcbi.1005992}, author = {Abdollahi, Nika and Albani, Alexandre and Anthony, Eric and Baud, Agnes and Cardon, M{\'e}lissa and Clerc, Robert and Czernecki, Dariusz and Conte, Romain and David, Laurent and Delaune, Agathe and Djerroud, Samia and Fourgoux, Pauline and Guiglielmoni, Nad{\`e}ge and Laurentie, Jeanne and Lehmann, Nathalie and Lochard, Camille and Montagne, R{\'e}mi and Myrodia, Vasiliki and Opuu, Vaitea and Parey, Elise and Polit, L{\'e}lia and Priv{\'e}, Sylvain and Quignot, Chlo{\'e} and Ruiz-Cuevas, Maria and Sissoko, Mariam and Sompairac, Nicolas and Vallerix, Audrey and Verrecchia, Violaine and Delarue, Marc and Gu{\'e}rois, Raphael and Ponty, Yann and S Sacquin-Mora and Carbone, Alessandra and Froidevaux, Christine and Le Crom, St{\'e}phane and Lespinet, Olivier and Weigt, Martin and Abboud, Samer and Bernardes, Juliana and Bouvier, Guillaume and Dequeker, Chlo{\'e} and Ferr{\'e}, Arnaud and Fuchs, Patrick and Lelandais, Ga{\"e}lle and Poulain, Pierre and Richard, Hugues and Schweke, Hugo and Laine, Elodie and Lopes, Anne} } @article {2018|2091, title = {MinOmics, an Integrative and Immersive Tool for Multi-Omics Analysis.}, journal = {J Integr Bioinform}, volume = {15}, year = {2018}, month = {2018 Jun 21}, abstract = {

Proteomic and transcriptomic technologies resulted in massive biological datasets, their interpretation requiring sophisticated computational strategies. Efficient and intuitive real-time analysis remains challenging. We use proteomic data on 1417 proteins of the green microalga Chlamydomonas reinhardtii to investigate physicochemical parameters governing selectivity of three cysteine-based redox post translational modifications (PTM): glutathionylation (SSG), nitrosylation (SNO) and disulphide bonds (SS) reduced by thioredoxins. We aim to understand underlying molecular mechanisms and structural determinants through integration of redox proteome data from gene- to structural level. Our interactive visual analytics approach on an 8.3 m2 display wall of 25 MPixel resolution features stereoscopic three dimensions (3D) representation performed by UnityMol WebGL. Virtual reality headsets complement the range of usage configurations for fully immersive tasks. Our experiments confirm that fast access to a rich cross-linked database is necessary for immersive analysis of structural data. We emphasize the possibility to display complex data structures and relationships in 3D, intrinsic to molecular structure visualization, but less common for omics-network analysis. Our setup is powered by MinOmics, an integrated analysis pipeline and visualization framework dedicated to multi-omics analysis. MinOmics integrates data from various sources into a materialized physical repository. We evaluate its performance, a design criterion for the framework.

}, keywords = {Algal Proteins, Chlamydomonas reinhardtii, Computer Graphics, Imaging, Three-Dimensional, Models, Structural, Oxidation-Reduction, Protein Conformation, Protein Interaction Maps, Protein Processing, Post-Translational, Proteome, Proteomics, Software, Virtual Reality}, issn = {1613-4516}, doi = {10.1515/jib-2018-0006}, author = {Maes, Alexandre and Martinez, Xavier and Druart, Karen and Laurent, Benoist and Gu{\'e}gan, Sean and Marchand, Christophe H and Lemaire, St{\'e}phane D and Marc Baaden} } @inbook {2018|2084, title = {The modelling and enhancement of water hydrodynamics: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {273-285}, issn = {1364-5498}, doi = {10.1039/c8fd90021c}, author = {Marc Baaden and Borthakur, Manash Pratim and Casanova, Serena and Coalson, Rob and Freger, Viatcheslav and Gonzalez, Miguel and G{\'o}ra, Artur and Hinds, Bruce and Hirunpinyopas, Wisit and Hummer, Gerhard and Kumar, Manish and Lynch, Charlotte and Murail, Samuel and Noy, Aleksandr and Sansom, Mark and Song, Qilei and Vashisth, Harish and V{\"o}gele, Martin} } @article {2018|2129, title = {Probing the quality control mechanism of the twin-arginine translocase with folding variants of a -designed heme protein.}, journal = {J Biol Chem}, volume = {293}, year = {2018}, month = {2018 05 04}, pages = {6672-6681}, abstract = {

Protein transport across the cytoplasmic membrane of bacterial cells is mediated by either the general secretion (Sec) system or the twin-arginine translocase (Tat). The Tat machinery exports folded and cofactor-containing proteins from the cytoplasm to the periplasm by using the transmembrane proton motive force as a source of energy. The Tat apparatus apparently senses the folded state of its protein substrates, a quality-control mechanism that prevents premature export of nascent unfolded or misfolded polypeptides, but its mechanistic basis has not yet been determined. Here, we investigated the innate ability of the model Tat system to recognize and translocate -designed protein substrates with experimentally determined differences in the extent of folding. Water-soluble, four-helix bundle maquette proteins were engineered to bind two, one, or no heme cofactors, resulting in a concomitant reduction in the extent of their folding, assessed with temperature-dependent CD spectroscopy and one-dimensional H NMR spectroscopy. Fusion of the archetypal N-terminal Tat signal peptide of the trimethylamine--oxide (TMAO) reductase (TorA) to the N terminus of the protein maquettes was sufficient for the Tat system to recognize them as substrates. The clear correlation between the level of Tat-dependent export and the degree of heme -induced folding of the maquette protein suggested that the membrane-bound Tat machinery can sense the extent of folding and conformational flexibility of its substrates. We propose that these artificial proteins are ideal substrates for future investigations of the Tat system\&$\#$39;s quality-control mechanism.

}, keywords = {Amino Acid Sequence, Bacterial Proteins, Circular Dichroism, Escherichia coli, Escherichia coli Proteins, Heme-Binding Proteins, Hemeproteins, Membrane Transport Proteins, Methylamines, Models, Molecular, Oxidoreductases, N-Demethylating, Periplasm, Protein Folding, Protein Sorting Signals, Protein Stability, Protein Transport, Proton Magnetic Resonance Spectroscopy, Substrate Specificity, Temperature}, issn = {1083-351X}, doi = {10.1074/jbc.RA117.000880}, author = {Sutherland, George A and Grayson, Katie J and Adams, Nathan B P and Mermans, Daphne M J and Jones, Alexander S and Robertson, Angus J and Auman, Dirk B and Brindley, Amanda A and Sterpone, Fabio and Tuffery, Pierre and Philippe Derreumaux and Dutton, P Leslie and Robinson, Colin and Hitchcock, Andrew and Hunter, C Neil} } @inbook {2018|2083, title = {Structure and function of natural proteins for water transport: general discussion.}, booktitle = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {83-95}, keywords = {Molecular Structure, Proteins, Water}, issn = {1364-5498}, doi = {10.1039/c8fd90019a}, author = {Marc Baaden and Barboiu, Mihail and Bill, Roslyn M and Casanova, Serena and Chen, Chun-Long and Conner, Matthew and Freger, Viatcheslav and Gong, Bing and G{\'o}ra, Artur and Hinds, Bruce and Horner, Andreas and Hummer, Gerhard and Kumar, Manish and Lokesh, Mahesh and Mitra, Sushanta and Noy, Aleksandr and Pohl, Peter and Sadet, Aude and Sansom, Mark and T{\"o}rnroth-Horsefield, Susanna and Vashisth, Harish} } @article {2017|2039, title = {A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against.}, journal = {Bioinform Biol Insights}, volume = {11}, year = {2017}, month = {2017}, pages = {1177932217712471}, abstract = {

We present an approach for detecting enzymes that are specific ofcompared withand provide targets that may assist research in drug development. This approach is based on traditional techniques of sequence homology comparison by similarity search and Markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. From 67 enzymes represented by 42 enzymatic activities classified by AnEnPi (Analogous Enzymes Pipeline) as specific forcompared with, only 40 (23 Enzyme Commission [EC] numbers) could actually be considered as strictly specific ofand 27 enzymes (19 EC numbers) were disregarded for having ambiguous homologies or analogies with. Among the 40 strictly specific enzymes, we identified sterol 24-C-methyltransferase, pyruvate phosphate dikinase, trypanothione synthetase, and RNA-editing ligase as 4 essential enzymes forthat may serve as targets for drug development.

}, issn = {1177-9322}, doi = {10.1177/1177932217712471}, author = {Catharina, Larissa and Lima, Carlyle Ribeiro and Franca, Alexander and Guimar{\~a}es, Ana Carolina Ramos and Alves-Ferreira, Marcelo and Tuffery, Pierre and Philippe Derreumaux and Carels, Nicolas} } @article {2017|2020, title = {Determinants of neuroglobin plasticity highlighted by joint coarse-grained simulations and high pressure crystallography}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {May}, pages = {1858}, author = {Colloc{\textquoteright}h, N. and S Sacquin-Mora and Avella, G. and Dhaussy, A. C. and Prange, T. and Vallone, B. and Girard, E.} } @article {2017|2026, title = {Tailoring protein nanomechanics with chemical reactivity}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {Jun}, pages = {15658}, abstract = {

The nanomechanical properties of elastomeric proteins determine the elasticity of a variety of tissues. A widespread natural tactic to regulate protein extensibility lies in the presence of covalent disulfide bonds, which significantly enhance protein stiffness. The prevalent in vivo strategy to form disulfide bonds requires the presence of dedicated enzymes. Here we propose an alternative chemical route to promote non-enzymatic oxidative protein folding via disulfide isomerization based on naturally occurring small molecules. Using single-molecule force-clamp spectroscopy, supported by DFT calculations and mass spectrometry measurements, we demonstrate that subtle changes in the chemical structure of a transient mixed-disulfide intermediate adduct between a protein cysteine and an attacking low molecular-weight thiol have a dramatic effect on the protein\&$\#$39;s mechanical stability. This approach provides a general tool to rationalize the dynamics of S-thiolation and its role in modulating protein nanomechanics, offering molecular insights on how chemical reactivity regulates protein elasticity.

}, doi = {10.1038/ncomms15658}, author = {Beedle, Amy E M and Mora, Marc and Lynham, Steven and Guillaume Stirnemann and Garcia-Manyes, Sergi} } @article {2017|2036, title = {VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants.}, journal = {Blood}, volume = {130}, year = {2017}, month = {2017 12 21}, pages = {2799-2807}, abstract = {

The first case of hereditary fibrinogen Aα-chain amyloidosis was recognized \>20 years ago, but disease mechanisms still remain unknown. Here we report detailed clinical and proteomics studies of a French kindred with a novel amyloidogenic fibrinogen Aα-chain frameshift variant, Phe521Leufs, causing a severe familial form of renal amyloidosis. Next, we focused our investigations to elucidate the molecular basis that render this Aα-chain variant amyloidogenic. We show that a 49-mer peptide derived from the C-terminal part of the Phe521Leufs chain is deposited as fibrils in the patient\&$\#$39;s kidneys, establishing that only a small portion of Phe521Leufs directly contributes to amyloid formation in vivo. In silico analysis indicated that this 49-mer Aα-chain peptide contained a motif (VLITL), with a high intrinsic propensity for β-aggregation at residues 44 to 48 of human renal fibrils. To experimentally verify the amyloid propensity of VLITL, we generated synthetic Phe521Leufs-derived peptides and compared their capacity for fibril formation in vitro with that of their VLITL-deleted counterparts. We show that VLITL forms typical amyloid fibrils in vitro and is a major signal for cross-β-sheet self-association of the 49-mer Phe521Leufs peptide identified in vivo, whereas its absence abrogates fibril formation. This study provides compelling evidence that VLITL confers amyloidogenic properties to Aα-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of Aα-chain amyloidosis.

}, keywords = {Amino Acid Motifs, Amino Acid Sequence, Amyloid, Amyloidosis, Familial, Fibrinogen, Frameshift Mutation, Humans, Kidney, Protein Conformation, beta-Strand}, issn = {1528-0020}, doi = {10.1182/blood-2017-07-796185}, author = {Garnier, Cyrille and Briki, Fatma and Nedelec, Brigitte and Le Pogamp, Patrick and Dogan, Ahmet and Rioux-Leclercq, Nathalie and Goude, Renan and Beugnet, Caroline and Martin, Laurent and Delpech, Marc and Bridoux, Frank and Grateau, Gilles and Doucet, Jean and Philippe Derreumaux and Valleix, Sophie} } @article {2017|2042, title = {What Can Human-Guided Simulations Bring to RNA Folding?}, journal = {Biophys J}, volume = {113}, year = {2017}, month = {2017 Jul 25}, pages = {302-312}, abstract = {

Inspired by the recent success of scientific-discovery games for predicting protein tertiary and RNA secondary structures, we have developed an open software for coarse-grained RNA folding simulations, guided by human intuition. To determine the extent to which interactive simulations can accurately predict 3D RNA structures of increasing complexity and lengths (four RNAs with 22-47 nucleotides), an interactive experiment was conducted with 141 participants who had very little knowledge of nucleic acids systems and computer simulations, and had received only a brief description of the important forces stabilizing RNA structures. Their structures and full trajectories have been analyzed statistically and compared to standard replica exchange molecular dynamics simulations. Our analyses show that participants gain easily chemical intelligence to fold simple and nontrivial topologies, with little computer time, and this result opens the door for the use of human-guided simulations to RNA folding. Our experiment shows that interactive simulations have better chances of success when the user widely explores the conformational space. Interestingly, providing on-the-fly feedback of the root mean square deviation with respect to the experimental structure did not improve the quality of the proposed models.

}, keywords = {Access to Information, Computer Simulation, Feedback, Psychological, Humans, Internet, Models, Genetic, Models, Molecular, RNA, RNA Folding, Software, Solvents}, issn = {1542-0086}, doi = {10.1016/j.bpj.2017.05.047}, author = {Mazzanti, Liuba and Doutreligne, S{\'e}bastien and Gageat, Cedric and Philippe Derreumaux and Antoine Taly and Marc Baaden and Pasquali, Samuela} } @article {2016|1711, title = {In silico structural characterization of protein targets for drug development against Trypanosoma cruzi}, journal = {J. Mol. Model.}, volume = {22}, number = {10}, year = {2016}, month = {oct}, abstract = {Trypanosoma cruzi is the protozoan pathogen responsible for Chagas disease, which is a major public health problem in tropical and subtropical regions of developing countries and particularly in Brazil. Despite many studies, there is no efficient treatment against Chagas disease, and the search for new therapeutic targets specific to T. cruzi is critical for drug development. Here, we have revisited 41 protein sequences proposed by the analogous enzyme pipeline, and found that it is possible to provide structures for T. cruzi sequences with clear homologs or analogs in H. sapiens and likely associated with trypanothione reductase, cysteine synthase, and ATPase functions, and structures for sequences specific to T. cruzi and absent in H. sapiens associated with 2,4-dienoyl-CoA reductase, and leishmanolysin activities. The implications of our structures refined by atomistic molecular dynamics (monomer or dimer states) in their in vitro environments (aqueous solution or membrane bilayers) are discussed for drug development and suggest that all protein targets, except cysteine synthase, merit further investigation.}, issn = {1610-2940}, doi = {10.1007/s00894-016-3115-9}, author = {Lima, Carlyle Ribeiro and Carels, Nicolas and Ramos Guimaraes, Ana Carolina and Pierre Tuffery and Philippe Derreumaux} } @article {2016|1750, title = {Non-equivalent binding sites for Abeta1-40 on PrP determine the oligomerisation pathway}, journal = {Prion}, volume = {10}, number = {1}, year = {2016}, pages = {S40}, issn = {1933-6896}, author = {Grznarova, Katarina and Torrent, Joan and Munoz-Montesino, Carola and Nasica, Jessica and Philippe Derreumaux and Beringue, Vincent and Deslys, Jean-Philippe and Rezaei, Human} } @article {2016|1672, title = {A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of gamma-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes.}, journal = {J. Biol. Chem}, volume = {291}, year = {2016}, month = {sep}, pages = {20473{\textendash}86}, abstract = {

Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured approximately 4\% of the synaptosomal proteome, including the unbiased capture of five alpha or beta GABAA receptor subunits. Lack of gamma2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for alpha/beta than gamma-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and alpha/beta cavity residues but not gamma cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity.

}, keywords = {anesthesia, anesthetic, click chemistry, GABA receptor, photoaffinity labeling}, doi = {10.1074/jbc.M116.736975}, author = {Woll, Kellie A. and Murlidaran, Sruthi and Pinch, Benika J. and J{\'e}r{\^o}me H{\'e}nin and Wang, Xiaoshi and Salari, Reza and Covarrubias, Manuel and Dailey, William P. and Grace Brannigan and Garcia, Benjamin A. and Roderic G Eckenhoff} } @article {2016|1633, title = {Water Determines the Structure and Dynamics of Proteins}, journal = {Chem. Rev.}, volume = {116}, year = {2016}, pages = {7673{\textendash}7697}, author = {M-C. Bellissent-Funel and A. Hassanali and M. Havenith and R. Henchman and P. Pohl and Fabio Sterpone and D. van der Spoel and Y. Xu and A. E. Garcia} } @article {2015|1667, title = {The adaptive biasing force method: everything you always wanted to know but were afraid to ask.}, journal = {J. Phys. Chem. B}, volume = {119}, year = {2015}, month = {jan}, pages = {1129{\textendash}51}, abstract = {

In the host of numerical schemes devised to calculate free energy differences by way of geometric transformations, the adaptive biasing force algorithm has emerged as a promising route to map complex free-energy landscapes. It relies upon the simple concept that as a simulation progresses, a continuously updated biasing force is added to the equations of motion, such that in the long-time limit it yields a Hamiltonian devoid of an average force acting along the transition coordinate of interest. This means that sampling proceeds uniformly on a flat free-energy surface, thus providing reliable free-energy estimates. Much of the appeal of the algorithm to the practitioner is in its physically intuitive underlying ideas and the absence of any requirements for prior knowledge about free-energy landscapes. Since its inception in 2001, the adaptive biasing force scheme has been the subject of considerable attention, from in-depth mathematical analysis of convergence properties to novel developments and extensions. The method has also been successfully applied to many challenging problems in chemistry and biology. In this contribution, the method is presented in a comprehensive, self-contained fashion, discussing with a critical eye its properties, applicability, and inherent limitations, as well as introducing novel extensions. Through free-energy calculations of prototypical molecular systems, many methodological aspects are examined, from stratification strategies to overcoming the so-called hidden barriers in orthogonal space, relevant not only to the adaptive biasing force algorithm but also to other importance-sampling schemes. On the basis of the discussions in this paper, a number of good practices for improving the efficiency and reliability of the computed free-energy differences are proposed.

}, issn = {1520-5207}, doi = {10.1021/jp506633n}, author = {Comer, Jeffrey and Gumbart, James C and J{\'e}r{\^o}me H{\'e}nin and Leli{\`e}vre, Tony and Pohorille, Andrew and Christophe Chipot} } @article {2015|1634, title = {Amyloid beta Protein and Alzheimer{\textquoteright}s Disease: When Computer Simulations Complement Experimental Studies}, journal = {Chem. Rev.}, volume = {115}, number = {9}, year = {2015}, month = {may}, pages = {3518{\textendash}3563}, doi = {10.1021/cr500638n}, author = {Nasica-Labouze, Jessica and Phuong Hoang Nguyen and Fabio Sterpone and Berthoumieu, Olivia and Buchete, Nicolae-Viorel and Cote, Sebastien and De Simone, Alfonso and Doig, Andrew J. and Faller, Peter and Garcia, Angel and Laio, Alessandro and Li, Mai Suan and Melchionna, Simone and Mousseau, Normand and Mu, Yuguang and Paravastu, Anant and Pasquali, Samuela and Rosenman, David J. and Strodel, Birgit and Tarus, Bogdan and Viles, John H. and Zhang, Tong and Wang, Chunyu and Philippe Derreumaux} } @article {2015|1975, title = {{A}llosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {112}, number = {9}, year = {2015}, month = {mar}, pages = {2865{\textendash}2870}, author = {Moraga-Cid, G. and Sauguet, L. and Huon, C. and Malherbe, L. and Girard-Blanc, C. and Petres, S. and Murail, S. and Antoine Taly and Marc Baaden and Delarue, M. and Corringer, P. J.} } @article {2015|1729, title = {The mechanochemistry of copper reports on the directionality of unfolding in model cupredoxin proteins.}, journal = {Nature Comm.}, volume = {6}, year = {2015}, pages = {7894}, abstract = {

Understanding the directionality and sequence of protein unfolding is crucial to elucidate the underlying folding free energy landscape. An extra layer of complexity is added in metalloproteins, where a metal cofactor participates in the correct, functional fold of the protein. However, the precise mechanisms by which organometallic interactions are dynamically broken and reformed on (un)folding are largely unknown. Here we use single molecule force spectroscopy AFM combined with protein engineering and MD simulations to study the individual unfolding pathways of the blue-copper proteins azurin and plastocyanin. Using the nanomechanical properties of the native copper centre as a structurally embedded molecular reporter, we demonstrate that both proteins unfold via two independent, competing pathways. Our results provide experimental evidence of a novel kinetic partitioning scenario whereby the protein can stochastically unfold through two distinct main transition states placed at the N and C termini that dictate the direction in which unfolding occurs.

}, isbn = {doi:10.1038/ncomms8894}, issn = {2041-1723}, doi = {10.1038/ncomms8894}, url = {http://www.nature.com/ncomms/2015/150803/ncomms8894/abs/ncomms8894.html}, author = {Beedle, Amy E M and Lezamiz, Ainhoa and Guillaume Stirnemann and Garcia-Manyes, Sergi} } @article {2015|1664, title = {Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.}, journal = {J. Membr. Biol.}, volume = {248}, year = {2015}, publisher = {Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527, Athens, Greece, zcournia@bioacademy.gr.}, chapter = {611}, abstract = {

Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

}, doi = {10.1007/s00232-015-9802-0}, author = {Cournia, Zoe and Allen, Toby W. and Andricioaei, Ioan and Antonny, Bruno and Baum, Daniel and Grace Brannigan and Buchete, Nicolae-Viorel and Deckman, Jason T. and Delemotte, Lucie and Del Val, Coral and Friedman, Ran and Gkeka, Paraskevi and Hege, Hans-Christian and J{\'e}r{\^o}me H{\'e}nin and Kasimova, Marina A. and Kolocouris, Antonios and Michael L Klein and Khalid, Syma and Lemieux, M Joanne and Lindow, Norbert and Roy, Mahua and Selent, Jana and Mounir Tarek and Tofoleanu, Florentina and Vanni, Stefano and Urban, Sinisa and Wales, David J. and Smith, Jeremy C. and Bondar, Ana-Nicoleta} } @conference {2015|1555, title = {UnityMol: interactive and ludic visual manipulation of coarse-grained RNA and other biomolecules}, booktitle = {Virtual and Augmented Reality for Molecular Science (VARMS@IEEEVR), 2015 IEEE 1st International Workshop on}, year = {2015}, month = {mar}, pages = {1{\textendash}6}, keywords = {biomolecular systems, coarse-grained RNA, collaborative research applications, data visualisation, feature extracti, HireRNA physics engine, interactive systems, Ludic visual manipulation, molecular biophysics, RNA, software architecture, teaching, UnityMol framework}, author = {S. Doutreligne and C. Gageat and T. Cragnolini and Antoine Taly and S. Pasquali and Philippe Derreumaux and Marc Baaden} } @conference {2015|1408, title = {Visualization of Biomolecular Structures: State of the Art}, booktitle = {Eurographics Conference on Visualization (EuroVis) - STARs}, year = {2015}, publisher = {The Eurographics Association}, organization = {The Eurographics Association}, author = {Kozlikova, Barbora and Krone, Michael and Lindow, Norbert and Falk, Martin and Marc Baaden and Baum, Daniel and Viola, Ivan and Parulek, Julius and Hege, Hans-Christian}, editor = {R. Borgo and F. Ganovelli and I. Viola} } @proceedings {2014|1577, title = {{BIOIMAGING} 2014 - Proceedings of the International Conference on Bioimaging, ESEO, Angers, Loire Valley, France, 3-6 March, 2014}, year = {2014}, publisher = {SciTePress}, editor = {M{\'a}rio Forjaz Secca and Jan Schier and Guy Plantier and Tanja Schultz and Ana L. N. Fred and Hugo Gamboa} } @article {2014|1964, title = {Interface Matters: The Stiffness Route to Stability of a Thermophilic Tetrameric Malate Dehydrogenase}, journal = {Plos One}, volume = {9}, number = {12}, year = {2014}, month = {dec}, pages = {e113895}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0113895}, author = {Kalimeri, Maria and Girard, Eric and Madern, Dominique and Sterpone, Fabio} } @article {2014|1637, title = {{L}ong distance effect on ligand-gated ion channels extracellular domain may affect interactions with the intracellular machinery}, journal = {Commun. Integr. Biol.}, volume = {7}, year = {2014}, pages = {e27984}, author = {Garret, M. and Boue-Grabot, E. and Antoine Taly} } @article {2014|1413, title = {{M}olecular simulations and visualization: introduction and overview}, journal = {Faraday Discuss.}, volume = {169}, year = {2014}, note = {[DOI:\href{http://dx.doi.org/10.1039/c4fd90024c}{10.1039/c4fd90024c}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25285906}{25285906}]}, pages = {9{\textendash}22}, author = {Hirst, J. D. and Glowacki, D. R. and Marc Baaden} } @conference {2014|1760, title = {Optogating a powerful approach to control an ion-channel gate}, booktitle = {PURINERGIC SIGNALLING}, volume = {10}, number = {4}, year = {2014}, pages = {762{\textendash}762}, publisher = {SPRINGER VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS}, organization = {SPRINGER VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS}, author = {Lemoine, Damien and Habermacher, Chlo{\'e} and Martz, Adeline and M{\'e}ry, Pierre-Fran\c cois and Bouquier, Nathalie and Diverchy, Fanny and Antoine Taly and Rassendren, Fran\c cois and Specht, Alexandre and Grutter, Thomas} } @article {2013|1699, title = {Agonist-dependent endocytosis of $\gamma$-aminobutyric acid type A (GABAA) receptors revealed by a $\gamma$2 (R43Q) epilepsy mutation}, journal = {J. Biol. Chem.}, volume = {288}, number = {39}, year = {2013}, pages = {28254{\textendash}28265}, publisher = {American Society for Biochemistry and Molecular Biology}, author = {Chaumont, Severine and Andr{\'e}, Caroline and Perrais, David and Bou{\'e}-Grabot, Eric and Antoine Taly and Garret, Maurice} } @article {2013|1752, title = {Elasticity, structure, and relaxation of extended proteins under force.}, journal = {Proc. Natl. Acad. Sci. U.s.a}, volume = {110}, year = {2013}, pages = {3847{\textendash}52}, abstract = {

Force spectroscopies have emerged as a powerful and unprecedented tool to study and manipulate biomolecules directly at a molecular level. Usually, protein and DNA behavior under force is described within the framework of the worm-like chain (WLC) model for polymer elasticity. Although it has been surprisingly successful for the interpretation of experimental data, especially at high forces, the WLC model lacks structural and dynamical molecular details associated with protein relaxation under force that are key to the understanding of how force affects protein flexibility and reactivity. We use molecular dynamics simulations of ubiquitin to provide a deeper understanding of protein relaxation under force. We find that the WLC model successfully describes the simulations of ubiquitin, especially at higher forces, and we show how protein flexibility and persistence length, probed in the force regime of the experiments, are related to how specific classes of backbone dihedral angles respond to applied force. Although the WLC model is an average, backbone model, we show how the protein side chains affect the persistence length. Finally, we find that the diffusion coefficient of the protein{\textquoteright}s end-to-end distance is on the order of 10(8) nm(2)/s, is position and side-chain dependent, but is independent of the length and independent of the applied force, in contrast with other descriptions.

}, keywords = {Atomic Force, Biophysical Phenomena, Computer Simulation, Elasticity, Mechanical, Microscopy, Models, Molecular, Molecular Dynamics Simulation, Proteins, Proteins: chemistry, Stress, Ubiquitin, Ubiquitin: chemistry}, issn = {1091-6490}, url = {http://www.pnas.org/content/early/2013/02/13/1300596110.abstract}, author = {Guillaume Stirnemann and Giganti, David and Fernandez, Julio M and Berne, B J} } @article {2013|1700, title = {Heme orientation modulates histidine dissociation and ligand binding kinetics in the hexacoordinated human neuroglobin}, journal = {J. Biol. Inorg. Chem.}, volume = {18}, number = {1}, year = {2013}, pages = {111{\textendash}122}, doi = {10.1007/s00775-012-0956-2}, author = {Bocahut, A. and Derrien, V. and Bernad, S. and Sebban, P. and S Sacquin-Mora and Guittet, E. and Lescop, E.} } @article {2013|1998, title = {{M}oving through the gate in {A}{T}{P}-activated {P}2{X} receptors}, journal = {Trends Biochem. Sci.}, volume = {38}, number = {1}, year = {2013}, month = {jan}, pages = {20{\textendash}29}, author = {Jiang, R. and Antoine Taly and Grutter, T.} } @article {2013|1770, title = {Moving through the gate in ATP-activated P2X receptors}, journal = {Trends Biochem. Sci.}, volume = {38}, number = {1}, year = {2013}, pages = {20{\textendash}29}, publisher = {Elsevier Current Trends}, author = {Jiang, Ruotian and Antoine Taly and Grutter, Thomas} } @article {2013|1747, title = {A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia}, journal = {Plos One}, volume = {8}, number = {1}, year = {2013}, publisher = {Public Library of Science}, author = {Ammar, A Ben and Soltanzadeh, Payam and Bauch{\'e}, St{\'e}phanie and Richard, Pascale and Goillot, Evelyne and Herbst, Ruth and Gaudon, Karen and Huz{\'e}, Caroline and Schaeffer, Laurent and Yamanashi, Yuji and others} } @article {2013|1973, title = {{O}ptical control of an ion channel gate}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {110}, number = {51}, year = {2013}, month = {dec}, pages = {20813{\textendash}20818}, author = {Lemoine, D. and Habermacher, C. and Martz, A. and Mery, P. F. and Bouquier, N. and Diverchy, F. and Antoine Taly and Rassendren, F. and Specht, A. and Grutter, T.} } @article {2013|1976, title = {Reassessing buried surface areas in protein-protein complexes.}, journal = {Protein Sci.}, volume = {22}, year = {2013}, month = {aug}, pages = {1453{\textendash}57}, abstract = {

The buried surface area (BSA), which measures the size of the interface in a protein-protein complex may differ from the accessible surface area (ASA) lost upon association (which we call DSA), if conformation changes take place. To evaluate the DSA, we measure the ASA of the interface atoms in the bound and unbound states of the components of 144 protein-protein complexes taken from the Protein-Protein Interaction Affinity Database of Kastritis et al. (2011). We observe differences exceeding 20\%, and a systematic bias in the distribution. On average, the ASA calculated in the bound state of the components is 3.3\% greater than in their unbound state, and the BSA, 7\% greater than the DSA. The bias is observed even in complexes where the conformation changes are small. An examination of the bound and unbound structures points to a possible origin: local movements optimize contacts with the other component at the cost of internal contacts, and presumably also the binding free energy.

}, keywords = {binding free energy, conformation changes, protein-protein interaction, solvent accessible surface}, doi = {10.1002/pro.2330}, author = {Chakravarty, Devlina and Guharoy, Mainak and Robert, Charles H. and Chakrabarti, Pinak and Janin, Jo{\"e}l} } @article {2013|1430, title = {{U}nderstanding small biomolecule-biomaterial interactions: a review of fundamental theoretical and experimental approaches for biomolecule interactions with inorganic surfaces}, journal = {J. Biomed. Mater. Res. A}, volume = {101}, number = {4}, year = {2013}, month = {apr}, pages = {1210{\textendash}1222}, author = {Costa, D. and Garrain, P. A. and Marc Baaden} } @article {2012|1911, title = {Delivering the native structures of peptides from computer simulations and predicted NMR proton chemical shifts}, journal = {J. Pept. Sci.}, volume = {18}, number = {1}, year = {2012}, month = {sep}, pages = {S38}, author = {Thevenet, P. and Shen, Y. and Maupetit, J. and Guyon, F. and Padilla, A. and Philippe Derreumaux and Pierre Tuffery} } @article {2012|1793, title = {{I}ntermediate closed channel state(s) precede(s) activation in the {A}{T}{P}-gated {P}2{X}2 receptor}, journal = {Channels (austin)}, volume = {6}, number = {5}, year = {2012}, pages = {398{\textendash}402}, author = {Jiang, R. and Antoine Taly and Lemoine, D. and Martz, A. and Specht, A. and Grutter, T.} } @article {2012|1756, title = {Involvement of the cysteine-rich head domain in activation and desensitization of the P2X1 receptor}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, number = {28}, year = {2012}, pages = {11396{\textendash}11401}, publisher = {National Acad Sciences}, author = {L{\"o}rinczi, {\'E}va and Bhargava, Yogesh and Marino, Stephen F and Antoine Taly and Kaczmarek-H{\'a}jek, Karina and Barrantes-Freer, Alonso and Dutertre, S{\'e}bastien and Grutter, Thomas and Rettinger, J{\"u}rgen and Nicke, Annette} } @article {2012|2004, title = {Ligand-gated ion channels: new insights into neurological disorders and ligand recognition}, journal = {Chem. Rev.}, volume = {112}, number = {12}, year = {2012}, month = {sep}, pages = {6285{\textendash}6318}, publisher = {American Chemical Society}, author = {Lemoine, Damien and Jiang, Ruotian and Antoine Taly and Chataigneau, Thierry and Specht, Alexandre and Grutter, Thomas} } @article {2012|1944, title = {PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides}, journal = {Nucleic Acids Res.}, volume = {40}, number = {W1}, year = {2012}, month = {jul}, pages = {W288-W293}, doi = {10.1093/nar/gks419}, author = {Thevenet, Pierre and Shen, Yimin and Maupetit, Julien and Guyon, Frederic and Philippe Derreumaux and Pierre Tuffery} } @article {2012|1753, title = {Rate limit of protein elastic response is tether dependent}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {109}, year = {2012}, pages = {14416{\textendash}14421}, abstract = {

The elastic restoring force of tissues must be able to operate over the very wide range of loading rates experienced by living organisms. It is surprising that even the fastest events involving animal muscle tissues do not surpass a few hundred hertz. We propose that this limit is set in part by the elastic dynamics of tethered proteins extending and relaxing under a changing load. Here we study the elastic dynamics of tethered proteins using a fast force spectrometer with sub-millisecond time resolution, combined with Brownian and Molecular Dynamics simulations. We show that the act of tethering a polypeptide to an object, an inseparable part of protein elasticity in vivo and in experimental setups, greatly reduces the attempt frequency with which the protein samples its free energy. Indeed, our data shows that a tethered polypeptide can traverse its free-energy landscape with a surprisingly low effective diffusion coefficient D(eff) \~{} 1,200 nm(2)/s. By contrast, our Molecular Dynamics simulations show that diffusion of an isolated protein under force occurs at D(eff) \~{} 10(8) nm(2)/s. This discrepancy is attributed to the drag force caused by the tethering object. From the physiological time scales of tissue elasticity, we calculate that tethered elastic proteins equilibrate in vivo with D(eff) \~{} 10(4)-10(6) nm(2)/s which is two to four orders magnitude smaller than the values measured for untethered proteins in bulk.

}, issn = {0027-8424}, author = {Berkovich, R. and Hermans, R. I. and Popa, I. and Guillaume Stirnemann and Garcia-Manyes, S. and Berne, B. J. and Fernandez, J. M.} } @article {2012|1995, title = {Structural and Spectroscopic Properties of Water around Small Hydrophobic Solutes}, journal = {The Journal of Physical Chemistry B}, volume = {116}, number = {38}, year = {2012}, pages = {11695{\textendash}11700}, doi = {10.1021/jp303213m}, author = {Montagna, Maria and Sterpone, Fabio and Guidoni, Leonardo} } @article {2012|2016, title = {{T}hermal fluctuations of haemoglobin from different species: adaptation to temperature via conformational dynamics}, journal = {J. R. Soc. Interface}, volume = {9}, number = {76}, year = {2012}, month = {nov}, pages = {2845{\textendash}2855}, doi = {10.1098/rsif.2012.0364}, author = {Stadler, A. M. and Garvey, C. J. and Bocahut, A. and S Sacquin-Mora and Digel, I. and Schneider, G. J. and Natali, F. and Artmann, G. M. and Zaccai, G.} } @article {2012|1805, title = {{T}ightening of the {A}{T}{P}-binding sites induces the opening of {P}2{X} receptor channels}, journal = {Embo J.}, volume = {31}, number = {9}, year = {2012}, month = {may}, pages = {2134{\textendash}2143}, author = {Jiang, R. and Antoine Taly and Lemoine, D. and Martz, A. and Cunrath, O. and Grutter, T.} } @article {2012|1816, title = {Theoretical study on a series of push-pull molecules grafted on methacrylate copolymers serving for nonlinear optics}, journal = {Int. J. Quantum Chem.}, volume = {112}, number = {15}, year = {2012}, month = {aug}, pages = {2735{\textendash}2742}, doi = {10.1002/qua.23299}, author = {Derrar, S. N. and Sekkal-Rahal, M. and Guemra, K. and Philippe Derreumaux} } @article {2011|1834, title = {{B}inding modes of noncompetitive {G}{A}{B}{A}-channel blockers revisited using engineered affinity-labeling reactions combined with new docking studies}, journal = {J. Agric. Food Chem.}, volume = {59}, number = {7}, year = {2011}, month = {apr}, pages = {2803{\textendash}2807}, author = {Charon, S. and Antoine Taly and Rodrigo, J. and Perret, P. and Goeldner, M.} } @article {2011|1665, title = {Community-wide assessment of protein-interface modeling suggests improvements to design methodology.}, journal = {J. Mol. Biol.}, volume = {414}, year = {2011}, month = {nov}, pages = {289{\textendash}302}, abstract = {

The CAPRI (Critical Assessment of Predicted Interactions) and CASP (Critical Assessment of protein Structure Prediction) experiments have demonstrated the power of community-wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community-wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting that there may be important physical chemistry missing in the energy calculations. A total of 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the nonpolar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were, on average, structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a nonbinder.

}, keywords = {Binding Sites, Models, Molecular, Protein Binding, Proteins}, issn = {1089-8638}, doi = {10.1016/j.jmb.2011.09.031}, author = {Fleishman, Sarel J and Whitehead, Timothy A and Strauch, Eva-Maria and Corn, Jacob E and Qin, Sanbo and Zhou, Huan-Xiang and Mitchell, Julie C and Demerdash, Omar N A and Takeda-Shitaka, Mayuko and Terashi, Genki and Moal, Iain H and Li, Xiaofan and Bates, Paul A and Martin Zacharias and Park, Hahnbeom and Ko, Jun-su and Lee, Hasup and Seok, Chaok and Bourquard, Thomas and Bernauer, Julie and Poupon, Anne and Az{\'e}, J{\'e}r{\^o}me and Soner, Seren and Ovali, Sefik Kerem and Ozbek, Pemra and Tal, Nir Ben and Haliloglu, T{\"u}rkan and Hwang, Howook and Vreven, Thom and Pierce, Brian G and Weng, Zhiping and P{\'e}rez-Cano, Laura and Pons, Carles and Fern{\'a}ndez-Recio, Juan and Jiang, Fan and Yang, Feng and Gong, Xinqi and Cao, Libin and Xu, Xianjin and Liu, Bin and Wang, Panwen and Li, Chunhua and Wang, Cunxin and Charles H. Robert and Guharoy, Mainak and Liu, Shiyong and Huang, Yangyu and Li, Lin and Guo, Dachuan and Chen, Ying and Xiao, Yi and London, Nir and Itzhaki, Zohar and Schueler-Furman, Ora and Inbar, Yuval and Potapov, Vladimir and Cohen, Mati and Schreiber, Gideon and Tsuchiya, Yuko and Kanamori, Eiji and Standley, Daron M and Nakamura, Haruki and Kinoshita, Kengo and Driggers, Camden M and Hall, Robert G and Morgan, Jessica L and Hsu, Victor L and Zhan, Jian and Yang, Yuedong and Zhou, Yaoqi and Kastritis, Panagiotis L and Bonvin, Alexandre M J J and Zhang, Weiyi and Camacho, Carlos J and Kilambi, Krishna P and Sircar, Aroop and Gray, Jeffrey J and Ohue, Masahito and Uchikoga, Nobuyuki and Matsuzaki, Yuri and Ishida, Takashi and Akiyama, Yutaka and Khashan, Raed and Bush, Stephen and Fouches, Denis and Tropsha, Alexander and Esquivel-Rodr{\'\i}guez, Juan and Kihara, Daisuke and Stranges, P Benjamin and Jacak, Ron and Kuhlman, Brian and Huang, Sheng-You and Zou, Xiaoqin and Wodak, Shoshana J and Janin, Jo{\"e}l and Baker, David} } @article {2011|1432, title = {Electrostatically{\textendash}driven fast association and perdeuteration allow transferred cross{\textendash}relaxation detection for G protein{\textendash}coupled receptor ligands with equilibrium dissociation constants in the high{\textendash}to{\textendash}low nanomolar range}, journal = {J Biomolecular Nmr}, volume = {50}, number = {3}, year = {2011}, month = {jul}, pages = {191{\textendash}5}, url = {http://www.ibpc.fr/UMR7099/Publis/pdf/Catoire11.pdf}, author = {L. J. Catoire and M. Damian and Marc Baaden and E. Guittet and J.-L. Ban{\`e}res} } @article {2011|2014, title = {{F}rom toxins targeting ligand gated ion channels to therapeutic molecules}, journal = {Toxins (basel)}, volume = {3}, number = {3}, year = {2011}, month = {mar}, pages = {260{\textendash}293}, publisher = {Molecular Diversity Preservation International}, author = {Nasiripourdori, A. and Taly, V. and Grutter, T. and Antoine Taly} } @article {2011|1972, title = {{A}gonist trapped in {A}{T}{P}-binding sites of the {P}2{X}2 receptor}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {108}, number = {22}, year = {2011}, month = {may}, pages = {9066{\textendash}9071}, author = {Jiang, R. and Lemoine, D. and Martz, A. and Antoine Taly and Gonin, S. and Prado de Carvalho, L. and Specht, A. and Grutter, T.} } @article {2011|1966, title = {Intrinsic Determinants of A beta(12-24) pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies}, journal = {Plos One}, volume = {6}, number = {9}, year = {2011}, month = {sep}, pages = {e24329}, doi = {10.1371/journal.pone.0024329}, author = {Xu, Weixin and Zhang, Ce and Philippe Derreumaux and Graslund, Astrid and Morozova-Roche, Ludmilla and Mu, Yuguang} } @article {2011|1587, title = {Mycoplasma gallisepticum produces a histone-like protein that recognizes base mismatches in DNA}, journal = {Biochemistry}, volume = {50}, year = {2011}, pages = {8692{\textendash}8702}, author = {Dmitri Kamashev and Jacques Oberto and Marina Serebryakova and Alexey Gorbachev and Yulia Zhukova and Sergei Levitskii and Alexey K Mazur and Vadim Govorun} } @article {2010|1524, title = {{H}ow cations can assist {D}{N}ase {I} in {D}{N}{A} binding and hydrolysis}, journal = {Plos Comput. Biol.}, volume = {6}, year = {2010}, month = {nov}, pages = {e1001000}, author = {M. Gueroult and D. Picot and J. Abi-Ghanem and B. Hartmann and Marc Baaden} } @article {2010|1516, title = {{M}ulti-resolution approach for interactively locating functionally linked ion binding sites by steering small molecules into electrostatic potential maps using a haptic device}, journal = {Pac. Symp. Biocomput.}, year = {2010}, pages = {205{\textendash}215}, author = {Delalande, O. and Nicolas F{\'e}rey and Laurent, B. and Gueroult, M. and Hartmann, B. and Marc Baaden} } @article {2010|1395, title = {{P}hotocontrol of protein activity in cultured cells and zebrafish with one- and two-photon illumination}, journal = {Chembiochem}, volume = {11}, year = {2010}, month = {mar}, pages = {653{\textendash}663}, author = {Sinha, D. K. and Neveu, P. and Gagey, N. and Aujard, I. and Benbrahim-Bouzidi, C. and Le Saux, T. and Rampon, C. and Gauron, C. and Goetz, B. and Dubruille, S. and Marc Baaden and Volovitch, M. and Bensimon, D. and Vriz, S. and Jullien, L.} } @article {2010|2007, title = {{A} putative extracellular salt bridge at the subunit interface contributes to the ion channel function of the {A}{T}{P}-gated {P}2{X}2 receptor}, journal = {J. Biol. Chem.}, volume = {285}, number = {21}, year = {2010}, month = {may}, pages = {15805{\textendash}15815}, publisher = {American Society for Biochemistry and Molecular Biology}, author = {Jiang, R. and Martz, A. and Gonin, S. and Antoine Taly and de Carvalho, L. P. and Grutter, T.} } @article {2010|1977, title = {Side-chain rotamer transitions at protein-protein interfaces}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {78}, year = {2010}, pages = {3219{\textendash}25}, author = {Mainak Guharoy and Jo\�el Janin and Charles H. Robert} } @article {2010, title = {The VLITL aggregation-prone motif might trigger amyloid fibril formation of fibrinogen A alpha-chain frameshift variants in vivo}, journal = {Amyloid-journal of Protein Folding Disorders}, volume = {17}, number = {Suppl. 1}, year = {2010}, note = {12th International Symposium on Amyloidosis from Molecular Mechanisms Toward the Cure of Systemic Amyloidoses, Rome, ITALY, APR 18-21, 2010}, pages = {96{\textendash}97}, author = {Valleix, S. and Philippe Derreumaux and Garnier, C. and Briki, F. and Boimard, M. and Doucet, J. and Rioux-Leclercq, N. and Martin, L. and Grateau, G. and Delpech, M. and Le Pogamp, P.} } @article {2009|1435, title = {{C}omplex molecular assemblies at hand via interactive simulations}, journal = {J. Comput. Chem.}, volume = {30}, year = {2009}, month = {nov}, pages = {2375{\textendash}2387}, author = {Delalande, O. and Nicolas F{\'e}rey and Grasseau, G. and Marc Baaden} } @article {2009|2010, title = {{N}icotinic receptors: allosteric transitions and therapeutic targets in the nervous system}, journal = {Nat. Rev. Drug Discov.}, volume = {8}, number = {9}, year = {2009}, month = {sep}, pages = {733{\textendash}750}, publisher = {Nature Publishing Group}, author = {Antoine Taly and Corringer, P. J. and Guedin, D. and Lestage, P. and Jean-Pierre Changeux} } @article {2009|1438, title = {{A}n optimized extended {D}{N}{A} kappa {B} site that enhances plasmid {D}{N}{A} nuclear import and gene expression}, journal = {J. Gene Med.}, volume = {11}, year = {2009}, month = {may}, pages = {401{\textendash}411}, author = {Goncalves, C. and Ardourel, M. Y. and Decoville, M. and Breuzard, G. and Midoux, P. and Hartmann, B. and Pichon, C.} } @article {2009|1779, title = {Role of nucleic acid binding in Sir3p-dependent interactions with chromatin fibers.}, journal = {Biochemistry}, volume = {48}, number = {2}, year = {2009}, month = {jan}, pages = {276{\textendash}288}, publisher = {Department of Biological Sciences and Cell Differentiation and Development Center, Marshall University, Huntington, West Virginia 25755, USA.}, abstract = {

Recent studies of the mechanisms involved in the regulation of gene expression in eukaryotic organisms depict a highly complex process requiring a coordinated rearrangement of numerous molecules to mediate DNA accessibility. Silencing in Saccharomyces cerevisiae involves the Sir family of proteins. Sir3p, originally described as repressing key areas of the yeast genome through interactions with the tails of histones H3 and H4, appears to have additional roles in that process, including involvement with a DNA binding component. Our in vitro studies focused on the characterization of Sir3p-nucleic acid interactions and their biological functions in Sir3p-mediated silencing using binding assays, EM imaging, and theoretical modeling. Our results suggest that the initial Sir3p recruitment is partially DNA-driven, highly cooperative, and dependent on nucleosomal features other than histone tails. The initial step appears to be rapidly followed by the spreading of silencing using linker DNA as a track.

}, doi = {10.1021/bi801705g}, author = {Nicholas L Adkins and Steve J McBryant and Cotteka N Johnson and Jennifer M Leidy and Christopher L Woodcock and Charles H Robert and Jeffrey C Hansen and Philippe T Georgel} } @article {2009|2019, title = {Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {75}, number = {4}, year = {2009}, month = {jun}, pages = {954{\textendash}963}, keywords = {Amino Acid Sequence, Amyloid beta-Protein, beta 2-Microglobulin, Cluster Analysis, Computer Simulation, Models, Molecular, Peptide Fragments, Protein Multimerization, Protein Structure, Secondary, Structure-Activity Relationship, Thermodynamics}, doi = {10.1002/prot.22305}, author = {Lu, Yan and Philippe Derreumaux and Guo, Zhi and Mousseau, Normand and Wei, Guanghong} } @article {2008|1583, title = {{C}omparative models of {P}2{X}2 receptor support inter-subunit {A}{T}{P}-binding sites}, journal = {Biochem. Biophys. Res. Commun.}, volume = {375}, number = {3}, year = {2008}, month = {oct}, pages = {405{\textendash}409}, author = {Guerlet, G. and Antoine Taly and Prado de Carvalho, L. and Martz, A. and Jiang, R. and Specht, A. and Le Novere, N. and Grutter, T.} } @article {2008|1585, title = {Comparative models of P2X2 receptor support inter-subunit ATP-binding sites}, journal = {Biochem. Biophys. Res. Commun.}, volume = {375}, number = {3}, year = {2008}, pages = {405{\textendash}409}, publisher = {Academic Press}, author = {Guerlet, Guillaume and Antoine Taly and De Carvalho, Lia Prado and Martz, Adeline and Jiang, Ruotian and Specht, Alexandre and Le Novere, Nicolas and Grutter, Thomas} } @article {2008|1434, title = {Dissecting the Hydrogen Bond: A Quantum Monte Carlo Approach}, journal = {J Chem Theo Comp}, volume = {4}, number = {9}, year = {2008}, pages = {1428{\textendash}1434}, author = {Sterpone, Fabio and Spanu, Leonardo and Ferraro, Luca and Sorella, Sandro and Guidoni, Leonardo} } @conference {2008|1557, title = {From Interactive to Immersive Molecular Dynamics}, booktitle = {Workshop on Virtual Reality Interaction and Physical Simulation (VRIPHYS 08 - Eurographics)}, year = {2008}, month = {nov}, pages = {89{\textendash}96}, address = {Grenoble - France}, author = {Nicolas F{\'e}rey and O. Delalande and G. Grasseau and Marc Baaden}, editor = {F. Faure and M. Teschner} } @article {2008|1515, title = {KNOTTIN: the knottin or inhibitor cystine knot scaffold in 2007}, journal = {Nucleic Acids Res.}, volume = {36}, number = {Sp. Iss. SI}, year = {2008}, month = {jan}, pages = {D314-D319}, keywords = {knottin}, author = {Gracy, Jerome and Le-Nguyen, Dung and Gelly, Jean-Christophe and Kaas, Quentin and Heitz, Annie and Chiche, Laurent} } @article {2008|1480, title = {Multiple-step virtual screening using VSM-G: Overview and validation of fast geometrical matching enrichment}, journal = {J. Mol. Model.}, volume = {14}, number = {5}, year = {2008}, pages = {393{\textendash}401}, author = {A Beautrait and V Leroux and Matthieu Chavent and L Ghemtio and M.-D Devignes and M Smail-Tabbone and W Cai and X Shao and G Moreau and P Bladon and J Yao and B Maigret} } @article {2008|1397, title = {Nonadiabatic vibrational dynamics and spectroscopy of peptides: A quantum-classical description}, journal = {Chem. Phys.}, volume = {347}, number = {1-3}, year = {2008}, month = {may}, pages = {208{\textendash}217}, author = {Kobus, Maja and Gorbunov, Roman D. and Phuong Hoang Nguyen and Stock, Gerhard} } @conference {2008|1545, title = {OPERA: An OPtimized coarsed-grained Energy model for RnA}, booktitle = {Publication Series of the John von Neumann Institute for Computing NIC Series}, volume = {40}, year = {2008}, pages = {185{\textendash}187}, author = {C. Colas and Phuong Hoang Nguyen and J-C. Gelly and Philippe Derreumaux} } @article {2008|1409, title = {Outer membrane proteins: comparing X-ray and NMR structures by MD simulations in lipid bilayers}, journal = {European Biophysics Journal with Biophysics Letters}, volume = {37}, number = {2}, year = {2008}, month = {feb}, pages = {131{\textendash}141}, author = {Cox, Katherine and Bond, Peter J. and Grottesi, Alessandro and Marc Baaden and Sansom, Mark S. P.} } @conference {2008|1553, title = {A VR Framework for Interacting with Molecular Simulations}, booktitle = {Symposium on Virtual Reality Software and Technology (ACM-VRST 2008)}, year = {2008}, month = {oct}, pages = {91{\textendash}94}, address = {Bordeaux - France}, author = {Nicolas F{\'e}rey and O. Delalande and G. Grasseau and Marc Baaden} } @article {2008|1678, title = {Water-water hydrogen bond studied by QMC}, journal = {J. Chem. Theory. Comput.}, volume = {4}, year = {2008}, pages = {1428{\textendash}1432}, author = {Fabio Sterpone and L. Spanu and L. Ferraro and S. Sorella and L. Guidoni} } @conference {2007|1517, title = {Atomistic modeling of the membrane-embedded synaptic fusion complex: a grand challenge project on the DEISA HPC infrastructure}, booktitle = {ParCo 2007, Parallel Computing: Architectures, Algorithms and Applications}, volume = {38}, year = {2007}, pages = {729{\textendash}736}, publisher = {John von Neumann Institute for Computing, Juelich, Germany.}, organization = {John von Neumann Institute for Computing, Juelich, Germany.}, url = {http://www.booksonline.iospress.nl/Content/View.aspx?piid=8468}, author = {E. Krieger and L. Leger and M.P. Durrieu and N. Taib and P. Bond and M. Laguerre and R. Lavery and M.S.P. Sansom and Marc Baaden}, editor = {C.B.G.R. Joubert and F. Peters and T. Lippert and M. Buecker and B. Gibbon and and B. Mohr} } @article {2007|1954, title = {{P}robing amyloid fibril formation of the {N}{F}{G}{A}{I}{L} peptide by computer simulations}, journal = {J. Chem. Phys.}, volume = {126}, number = {6}, year = {2007}, month = {feb}, pages = {065101}, doi = {10.1063/1.2435358}, author = {Melquiond, A. and Gelly, J.C. and Mousseau, N. and Philippe Derreumaux} } @article {2007|1728, title = {{A} prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family}, journal = {Nature}, volume = {445}, number = {7123}, year = {2007}, month = {jan}, pages = {116{\textendash}119}, author = {Bocquet, N. and Prado de Carvalho, L. and Cartaud, J. and Neyton, J. and Le Poupon, C. and Antoine Taly and Grutter, T. and Jean-Pierre Changeux and Corringer, P. J.} } @article {2007|1467, title = {Quantum-classical description of the amide I vibrational spectrum of trialanine}, journal = {J. Chem. Phys.}, volume = {126}, number = {5}, year = {2007}, month = {feb}, author = {Gorbunov, Roman D. and Phuong Hoang Nguyen and Kobus, Maja and Stock, Gerhard} } @conference {2007|1491, title = {REVIVOS: REalit{\'e} VIrtuelle pour la construction de VOcabulaires Sp{\'e}cialis{\'e}s}, booktitle = {Journ{\'e}es Francophones d{\textquoteright}Ing{\'e}nierie des Connaissances (AFIA-IC 2007)}, year = {2007}, month = {jul}, address = {Grenoble - France}, author = {Nicolas F{\'e}rey and Claire Toffano-Nioche and Oriane Matte-Taillez and Rachid Gherbi and William Turner} } @article {2007|1489, title = {Structure and dynamics of the homologous series of alanine peptides: A joint molecular dynamics/NMR study}, journal = {J. Am. Chem. Soc.}, volume = {129}, number = {5}, year = {2007}, month = {feb}, pages = {1179{\textendash}1189}, author = {Graf, Juergen and Phuong Hoang Nguyen and Stock, Gerhard and Schwalbe, Harald} } @article {2006|1935, title = {HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription.}, journal = {Mol. Cell}, volume = {22}, number = {5}, year = {2006}, month = {jun}, pages = {669{\textendash}679}, publisher = {Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Building 41, B602, Bethesda, Maryland 20892, USA.}, abstract = {Although histone deacetylases (HDACs) are generally viewed as corepressors, we show that HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). Furthermore, a subfraction of cellular HDAC1 is acetylated after association with the GR, and this acetylation event correlates with a decrease in promoter activity. HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of acetylation. Acetylation of purified HDAC1 inactivates its deacetylase activity, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. We propose that hormone activation of the receptor leads to progressive acetylation of HDAC1 in vivo, which in turn inhibits the deacetylase activity of the enzyme and prevents a deacetylation event that is required for promoter activation. These findings indicate that HDAC1 is required for the induction of some genes by the GR, and this activator function is dynamically modulated by acetylation.}, keywords = {Acetylation, Amino Acid Sequence, Animals, Binding Sites, Cell Cycle Proteins, Chromatin, Down-Regulation, genetics/metabolism, Hela Cells, Histone Acetyltransferases, Histone Deacetylases, Humans, immunology/metabolism, metabolism}, doi = {10.1016/j.molcel.2006.04.019}, author = {Yi Qiu and Yingming Zhao and Matthias Becker and Sam John and Bhavin S Parekh and Suming Huang and Anindya Hendarwanto and Elisabeth D Martinez and Yue Chen and Hanxin Lu and Nicholas L Adkins and Diana A Stavreva and Malgorzata Wiench and Philippe T Geor} } @article {2006|2008, title = {{I}dentification of two critical residues within the {C}ys-loop sequence that determine fast-gating kinetics in a pentameric ligand-gated ion channel}, journal = {J. Mol. Neurosci.}, volume = {30}, number = {1-2}, year = {2006}, pages = {63{\textendash}64}, publisher = {Springer}, author = {Grutter, T. and de Carvalho, L. P. and Dufresne, V. and Antoine Taly and Jean-Pierre Changeux} } @article {2006|1754, title = {{I}mplications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {103}, number = {45}, year = {2006}, month = {nov}, pages = {16965{\textendash}16970}, author = {Antoine Taly and Corringer, P. J. and Grutter, T. and Prado de Carvalho, L. and Karplus, M. and Jean-Pierre Changeux} } @article {2006|1497, title = {An Immersive Visualization and Interaction Paradigm for Genomic Databases Exploration}, journal = {Mediterranean Journal of Computers and Networks}, volume = {2}, number = {3}, year = {2006}, month = {jul}, pages = {118{\textendash}124}, author = {Nicolas F{\'e}rey and P.-E. Gros and R. Gherbi} } @article {2006|1757, title = {Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors}, journal = {Proceedings of the National Academy of Sciences}, volume = {103}, number = {45}, year = {2006}, pages = {16965{\textendash}16970}, publisher = {National Acad Sciences}, author = {Antoine Taly and Corringer, Pierre-Jean and Grutter, Thomas and De Carvalho, Lia Prado and Karplus, Martin and Jean-Pierre Changeux} } @article {2006|1389, title = {Photoinduced conformational dynamics of a photoswitchable peptide: A nonequilibrium molecular dynamics simulation study}, journal = {Biophys. J.}, volume = {91}, number = {4}, year = {2006}, month = {aug}, pages = {1224{\textendash}1234}, author = {Phuong Hoang Nguyen and Gorbunov, Roman D. and Stock, Gerhard} } @article {2006|1514, title = {Protein Peeling 2: a web server to convert protein structures into series of protein units}, journal = {Nucleic Acids Res.}, volume = {34}, number = {Sp. Iss. SI}, year = {2006}, month = {jul}, pages = {W75-W78}, author = {Gelly, J. -C. and Etchebest, C. and Hazout, S. and de Brevern, A. G.} } @article {2006|1386, title = {{\textquoteleft}Protein Peeling{\textquoteright}: an approach for splitting a 3D protein structure into compact fragments}, journal = {Bioinformatics}, volume = {22}, number = {2}, year = {2006}, pages = {129{\textendash}133}, author = {Gelly, JC and de Brevern, AG and Hazout, S} } @conference {2006|1424, title = {Visual Mining for Microarray Knowledge Discovery}, booktitle = {International Conference on Information \& Communication Technologies: from Theory to Applications (ICTTA 2006 - IEEE)}, year = {2006}, month = {apr}, address = {Damascus - Syria}, author = {Nicolas F{\'e}rey and R. Gherbi} } @conference {2006|1421, title = {Yeast Naked DNA Spatial Organization Predisposes to Transcriptional Regulation}, booktitle = {International Conference on Computational Science and its Applications (ICCSA 2006)}, volume = {3984}, year = {2006}, month = {may}, pages = {222{\textendash}231}, address = {Glasgow, United Kingdom}, author = {O. Matte-Tailliez and J .H{\'e}risson and Nicolas F{\'e}rey and O. Magneau and P.-E. Gros and F. K{\'e}p{\`e}s and R. Gherbi} } @article {2005|1631, title = {{A} chimera encoding the fusion of an acetylcholine-binding protein to an ion channel is stabilized in a state close to the desensitized form of ligand-gated ion channels}, journal = {C. R. Biol.}, volume = {328}, number = {3}, year = {2005}, month = {mar}, pages = {223{\textendash}234}, author = {Grutter, T. and Prado de Carvalho, L. and Virginie, D. and Antoine Taly and Fischer, M. and Jean-Pierre Changeux} } @article {2005|1775, title = {Chromatin remodeling complexes: ATP-dependent machines in action.}, journal = {Biochem. Cell Biol.}, volume = {83}, number = {4}, year = {2005}, month = {aug}, pages = {405{\textendash}417}, publisher = {Division of Biological Sciences, Marshall University, Huntington, WV 25755, USA.}, abstract = {Since the initial characterization of chromatin remodeling as an ATP-dependent process, many studies have given us insight into how nucleosome-remodeling complexes can affect various nuclear functions. However, the multistep DNA-histone remodeling process has not been completely elucidated. Although new studies are published on a nearly weekly basis, the nature and roles of interactions of the individual SWI/SNF- and ISWI-based remodeling complexes and DNA, core histones, and other chromatin-associated proteins are not fully understood. In addition, the potential changes associated with ATP recruitment and its subsequent hydrolysis have not been fully characterized. This review explores possible mechanisms by which chromatin-remodeling complexes are recruited to specific loci, use ATP hydrolysis to achieve actual remodeling through disruption of DNA-histone interactions, and are released from their chromatin template. We propose possible roles for ATP hydrolysis in a chromatin-release/target-scanning process that offer an alternative to or complement the often overlooked function of delivering the energy required for sliding or dislodging specific subsets of core histones.}, keywords = {Adenosine Triphosphatases, Adenosine Triphosphate, Animals, Chromatin, Gene Expression Regulation, genetics/metabolism, Humans, metabolism, Nucleosomes, Transcription Factors}, doi = {10.1139/o05-115}, author = {Cotteka N Johnson and Nicholas L Adkins and Philippe Georgel} } @article {2005|1391, title = {EvDTree: structure-dependent substitution profiles based on decision tree classification of 3D environments}, journal = {Bmc Bioinf.}, volume = {6}, year = {2005}, month = {jan}, author = {Gelly, JC and Chiche, L and Gracy, J} } @article {2005|1405, title = {Immersive graph-based visualization and exploration of biological data relationships}, journal = {Data Sci. J.}, volume = {4}, year = {2005}, month = {mar}, pages = {189{\textendash}194}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2005|1900, title = {Improved greedy algorithm for protein structure reconstruction}, journal = {J. Comput. Chem.}, volume = {26}, number = {5}, year = {2005}, month = {apr}, pages = {506{\textendash}513}, doi = {10.1002/jcc.20181}, author = {Pierre Tuffery and Guyon, F and Philippe Derreumaux} } @article {2005|2011, title = {{M}olecular tuning of fast gating in pentameric ligand-gated ion channels}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {102}, number = {50}, year = {2005}, month = {dec}, pages = {18207{\textendash}18212}, publisher = {National Acad Sciences}, author = {Grutter, T. and de Carvalho, L. P. and Dufresne, V. and Antoine Taly and Edelstein, S. J. and Jean-Pierre Changeux} } @article {2005|1508, title = {Modular RNA architecture revealed by computational analysis of existing pseudoknots and ribosomal RNAs}, journal = {Nuc. Acids Res.}, volume = {33}, year = {2005}, pages = {1384{\textendash}1398}, author = {S. Pasquali and H.H. Gan and T. Schlick} } @article {2005|2003, title = {{N}ormal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism}, journal = {Biophys. J.}, volume = {88}, number = {6}, year = {2005}, month = {jun}, pages = {3954{\textendash}3965}, publisher = {Cell Press}, author = {Antoine Taly and Delarue, M. and Grutter, T. and Nilges, M. and Le Novere, N. and Corringer, P. J. and Jean-Pierre Changeux} } @article {2005|1952, title = {Navigation and analysis of the energy landscape of small proteins using the activation-relaxation technique}, journal = {Phys. Biol.}, volume = {2}, number = {4, Sp. Iss. SI}, year = {2005}, month = {dec}, pages = {S101-S107}, doi = {10.1088/1478-3975/2/4/S04}, author = {Mousseau, N and Philippe Derreumaux and Gilbert, G} } @conference {2005|1422, title = {Visual data mining of genomic databases by immersive graph-based exploration}, booktitle = {international Conference on Computer Graphics and interactive Techniques in Australasia and South East Asia (GRAPHITE 2005 - ACM-ACMSIGRAPH Sponsored)}, year = {2005}, month = {nov}, pages = {143{\textendash}146}, address = {Dunedin - New Zealand}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1815, title = {Combining Applications and Databases Integration Approaches in a Common Distributed Genomic Platform}, booktitle = {International CODATA Conference, The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, publisher = {Tamkang University}, organization = {Tamkang University}, address = {Berlin, Germany}, author = {P.-E. Gros and J. H{\'e}risson and Nicolas F{\'e}rey and R. Gherbi} } @conference {2004|1420, title = {A Distributed Multimedia Database Visualization within An Immersive Environment for Bioinformatics}, booktitle = {International Symposium on Multimedia Software Engineering (ISMSE 2004 - IEEE)}, year = {2004}, month = {dec}, pages = {156{\textendash}159}, address = {Miami - USA}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1425, title = {DNA in Virtuo: Visualization and Exploration of 3D Genomic Structures}, booktitle = {International Conference on Virtual Reality, Computer Graphics, Visualization and Interaction (Afrigraph 2005 - ACM-SIGRAPH sponsored)}, year = {2004}, month = {nov}, address = {Stellenbosch (Cap town), South Africa}, author = {J. H{\'e}risson and P.-E. Gros and Nicolas F{\'e}rey and O. Magneau and R. Gherbi} } @conference {2004|1419, title = {DNA in Virtuo: Visualization and Virtual Manipulation of 3D Genomic Structures}, booktitle = {International CODATA Conference, The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, address = {Berlin, Germany}, author = {J. H{\'e}risson and P.-E. Gros and Nicolas F{\'e}rey and O. Magneau and R. Gherbi} } @article {2004|1462, title = {Exploration by visualization of numerical and textual genomic data}, journal = {Journal of Biological Physics and Chemistry}, volume = {4}, number = {2}, year = {2004}, month = {jun}, pages = {102{\textendash}110}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @conference {2004|1423, title = {GenoMEDIA, a Midlleware Platform for Distributed Genomic Information}, booktitle = {International Conference on Information \& Communication Technologies: from Theory to Applications (ICTTA 2004 - IEEE)}, year = {2004}, month = {apr}, address = {Damascus - Syria}, author = {P.-E. Gros and Nicolas F{\'e}rey and J. H{\'e}risson and R. Gherbi} } @conference {2004|1418, title = {Immersive Graph-based Visualization and Exploration of Biological Data}, booktitle = {International CODATA Conference - The Information Society: New Horizons for Science}, year = {2004}, month = {nov}, address = {Berlin - Germany}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2004|1513, title = {The KNOTTIN website and database: a new information system dedicated to the knottin scaffold}, journal = {Nucleic Acids Res.}, volume = {32}, number = {Sp. Iss. SI}, year = {2004}, month = {jan}, pages = {D156-D159}, author = {Gelly, JC and Gracy, J and Kaas, Q and Le-Nguyen, D and Heitz, A and Chiche, L} } @article {2004|1404, title = {Squash inhibitors: From structural motifs to macrocyclic knottins}, journal = {Current Protein \& Peptide Science}, volume = {5}, number = {5}, year = {2004}, pages = {341{\textendash}349}, author = {Chiche, L and Heitz, A and Gelly, JC and Gracy, J and Chau, PTT and Ha, PT and Hernandez, JF and Le-Nguyen, D} } @conference {2004|1492, title = {Visualization and Exploration of Factual and Textual Genomic Data}, booktitle = {Journ{\'e}es Ouvertes de Biologie, Informatique et Math{\'e}matiques (JOBIM 2004)}, year = {2004}, month = {jun}, address = {Montr{\'e}al - Canada}, author = {Nicolas F{\'e}rey and P.-E. Gros and J. H{\'e}risson and R. Gherbi} } @article {2003|1507, title = {Exploring The Repertoire of RNA Secondary Motifs Using Graph Theory with Implications for RNA Design}, journal = {Nuc. Acids Res.}, volume = {31}, year = {2003}, pages = {2926{\textendash}2943}, author = {H. H. Gan and S. Pasquali and and T. Schlick} } @article {2003|1914, title = {Generating conformations for two zinc-binding sites of HIV-1 nucleocapsid protein from random conformations by a hierarchical procedure and polarizable force field}, journal = {J. Phys. Chem. B}, volume = {107}, number = {20}, year = {2003}, month = {may}, pages = {4862{\textendash}4870}, doi = {10.1021/jp022527z}, author = {Gresh, N and Philippe Derreumaux} } @article {2002, title = {Analysis of Protein Sequence/Structure Similarity Relationships}, journal = {Biophys. J.}, volume = {83}, year = {2002}, pages = {2781{\textendash}2791}, author = {H. H. Gan and R. A. Perow and S. Roy and J. Ko, M. Wu, J. Huang and S. Yan and A. Nicoletta and J. Vafai, D. Sun and L. Wang and J. E. Noah and S. Pasquali and T. Schlick} } @conference {2002|1622, title = {Cd2+ binding effect on bacterial reaction center mutants: The proton penetration involves interdependent pathways}, booktitle = {BIOPHYSICAL JOURNAL}, volume = {82}, number = {1}, year = {2002}, pages = {518A-518A}, publisher = {BIOPHYSICAL SOCIETY 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA}, organization = {BIOPHYSICAL SOCIETY 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA}, author = {Gerencser, L and Antoine Taly and Baciou, L and Maroti, P and Sebban, P} } @article {2002|1790, title = {Differential core histone binding behavior: {R}{N}{A} polymerase {I} promoter region vs 5{S} r{D}{N}{A} positioning {D}{N}{A} sequences}, journal = {Cell Biochem. Biophys.}, volume = {37}, number = {1}, year = {2002}, pages = {1{\textendash}13}, author = {Georgel, Philippe T and Robert, Charles H} } @article {2002|1402, title = {The direct correlation function in nematic liquid crystals from computer simulation}, journal = {Comput. Phys. Commun.}, volume = {147}, number = {1-2}, year = {2002}, note = {Europhysics Conference on Computational Physics (CCP 2001), AACHEN, GERMANY, SEP 05-08, 2001}, month = {aug}, pages = {350{\textendash}353}, author = {Phuong, NH and Germano, G and Schmid, F} } @article {2002|2002, title = {{E}ffect of binding of {C}d2+ on bacterial reaction center mutants: proton-transfer uses interdependent pathways}, journal = {Biochemistry}, volume = {41}, number = {29}, year = {2002}, month = {jul}, pages = {9132{\textendash}9138}, publisher = {ACS Publications}, author = {Gerencser, L. and Antoine Taly and Baciou, L. and Maroti, P. and Sebban, P.} } @article {2002|1599, title = {New insights into the allosteric mechanism of human hemoglobin from molecular dynamics simulations}, journal = {Biophys. J.}, volume = {82}, number = {6}, year = {2002}, month = {jun}, pages = {3224{\textendash}3245}, author = {Mouawad, Liliane and Perahia, David and Charles H. Robert and Guilbert, Christophe} } @article {2001|1463, title = {Elastic constants from direct correlation functions in nematic liquid crystals: A computer simulation study}, journal = {J. Chem. Phys.}, volume = {115}, number = {15}, year = {2001}, month = {oct}, pages = {7227{\textendash}7234}, author = {Phuong, NH and Germano, G and Schmid, F} } @article {2001|1461, title = {Induction-independent recruitment of CREB-binding protein to the c-fos serum response element through interactions between the bromodomain and Elk-1}, journal = {J. Biol. Chem.}, volume = {276}, number = {7}, year = {2001}, month = {feb}, pages = {5213{\textendash}5221}, author = {Nissen, LJ and Gelly, JC and Hipskind, RA} } @article {2001|1841, title = {Sheep prion protein synthetic peptide spanning helix 1 and beta-strand 2 (residues 142-166) shows beta-hairpin structure in solution}, journal = {J. Biol. Chem.}, volume = {276}, number = {49}, year = {2001}, pages = {46364{\textendash}46370}, author = {S. A. Kozin and G. Bertho and Alexey K Mazur and H. Rabesona and J. P. Girault and T. Haertle and M. Takahashi and P. Debey and G. H. Hoa} } @article {2000|1501, title = {Dependence of NMR isotropic shift averages and nuclear shielding tensors on the internal rotation of the functional group X about the C-X bond in seven simple vinylic derivatives H2C=CH-X}, journal = {Mol. Phys.}, volume = {98}, number = {6}, year = {2000}, month = {mar}, pages = {329{\textendash}342}, author = {Marc Baaden and Granger, P and Strich, A} } @inbook {2000|1559, title = {Interfacial features of assisted liquid-liquid extraction of uranyl and cesium salts: a molecular dynamics investigation}, booktitle = {ACS Symposium Series 757}, year = {2000}, pages = {71{\textendash}85}, publisher = {Oxford University Press, New York}, organization = {Oxford University Press, New York}, chapter = {Calixarenes for separations}, author = {Marc Baaden and F. Berny and N. Muzet and L. Troxler and G. Wipff}, editor = {G. Lumetta, R.D. Rogers, and A.S. Gopalan} } @article {1997|1680, title = {Collective-variable Monte Carlo simulation of DNA}, journal = {J. Comp. Chem.}, volume = {18}, year = {1997}, pages = {2001{\textendash}2011}, author = {H. Gabb and Chantal Pr{\'e}vost and G. Bertucat and Charles H. Robert and Richard Lavery} } @article {1996|1666, title = {Finding and visualizing nucleic acid base stacking}, journal = {J Mol Graph}, volume = {14}, number = {1}, year = {1996}, month = {feb}, pages = {6{\textendash}11}, author = {Gabb, H A and Sanghani, S R and Charles H. Robert and Chantal Pr{\'e}vost} } @article {1995|1681, title = {Efficient conformational space sampling for nucleosides using internal coordinate Monte-Carlo simulations and a modified furanose description}, journal = {J. Comput. Chem.}, volume = {16}, year = {1995}, month = {jun}, pages = {667{\textendash}680}, chapter = {667}, abstract = {

Internal coordinates can be very helpful in modeling large biomacromolecules because freezing stiffer degrees of freedom, such as bond lengths, strongly reduces the number of variables describing the system. This, however, leads to difficulties in treating flexible rings such as the furanose sugars of nucleic acids or the proline residues of proteins, for which internal coordinates are an overcomplete description. We present here a new, internal coordinate furanose model based on the pseudorotational variables phase and amplitude which avoids having to solve a ring closure problem. The choice of a two- rather than a four-variable description is justified by a detailed analysis of molecular dynamic simulations. The efficiency and accuracy of the method are also demonstrated using extensive Monte Carlo simulations. This method of ring treatment is fast and well adapted to macromolecular simulations. (C) 1995 by John Wiley \& Sons, Inc.

}, issn = {0192-8651}, author = {Gabb, HA and Richard Lavery and Chantal Pr{\'e}vost} } @article {1989|1785, title = {Allosteric formulation of thermal transitions in macromolecules, including effects of ligand binding and oligomerization}, journal = {Biopolymers}, volume = {28}, number = {10}, year = {1989}, month = {oct}, pages = {1705{\textendash}1729}, author = {Robert, C H and Colosimo, A and Gill, S J} } @article {1989|1821, title = {Binding of oxygen and carbon monoxide to the hemocyanin from the spiny lobster}, journal = {J. Mol. Biol.}, volume = {207}, number = {4}, year = {1989}, month = {jun}, pages = {829{\textendash}832}, author = {Connelly, P R and Johnson, C R and Robert, C H and Bak, H J and Gill, S J} } @article {1988|1597, title = {Analysis and parameter resolution in highly cooperative systems}, journal = {Biophys. Chem.}, volume = {30}, number = {2}, year = {1988}, month = {jun}, pages = {133{\textendash}141}, author = {Gill, S J and Connelly, P R and Di Cera, E and Charles H. Robert} } @inbook {1988, title = {Analysis of allosteric systems}, booktitle = {Biochemical Thermodynamics}, year = {1988}, publisher = {Elsevier}, organization = {Elsevier}, edition = {2nd}, address = {Holland}, author = {Gill, S. J. and Robert, C. H. and Wyman, J.} } @article {1988|1858, title = {Enthalpy of dimerization of benzene in water}, journal = {J. Phys. Chem.}, volume = {92}, year = {1988}, pages = {3623{\textendash}3625}, author = {D. Hallen and I. Wadso and D. J. Wasserman and C. H. Robert and S. J. Gill} } @article {1988|1589, title = {Linkage of organic phosphates to oxygen binding in human hemoglobin at high concentrations}, journal = {Biochemistry}, volume = {27}, number = {18}, year = {1988}, month = {sep}, pages = {6835{\textendash}6843}, author = {Charles H. Robert and Fall, L and Gill, S J} } @article {1988|1590, title = {Nested allosteric interaction in tarantula hemocyanin revealed through the binding of oxygen and carbon monoxide}, journal = {Biochemistry}, volume = {27}, number = {18}, year = {1988}, month = {sep}, pages = {6901{\textendash}6908}, author = {Decker, H and Connelly, P R and Charles H. Robert and Gill, S J} } @article {1988|1591, title = {Quantitative analysis of linkage in macromolecules when one ligand is present in limited total quantity}, journal = {Biochemistry}, volume = {27}, number = {18}, year = {1988}, month = {sep}, pages = {6829{\textendash}6835}, author = {Charles H. Robert and Gill, S J and Wyman, J} } @article {1987|1777, title = {Allosteric interpretation of the oxygen-binding reaction of human hemoglobin tetramers}, journal = {Biochemistry}, volume = {26}, number = {13}, year = {1987}, month = {jun}, pages = {4003{\textendash}4008}, author = {Di Cera, E and Robert, C H and Gill, S J} } @inbook {1987, title = {Calorimetric analysis of oxygen binding to lobster hemocyanin}, booktitle = {Invertebrate Oxygen Carriers}, year = {1987}, publisher = {Springer-Verlag}, organization = {Springer-Verlag}, address = {Berlin}, author = {Parody-Morreale, A. and Robert, C. H. and Gill, S. J.} } @article {1987|1818, title = {Calorimetric studies of oxygen and carbon monoxide binding to human hemoglobin. Sequential binding heats for oxygen}, journal = {J. Biol. Chem.}, volume = {262}, number = {23}, year = {1987}, month = {aug}, pages = {10994{\textendash}10999}, author = {Parody-Morreale, A and Robert, C H and Bishop, G A and Gill, S J} } @article {1987|1820, title = {Carbon dioxide and oxygen linkage in human hemoglobin tetramers}, journal = {J. Mol. Biol.}, volume = {196}, number = {4}, year = {1987}, month = {aug}, pages = {927{\textendash}934}, author = {Doyle, M L and Di Cera, E and Robert, C H and Gill, S J} } @article {1987|1991, title = {Gas-solution microcalorimeter for determining heat binding curves}, journal = {Rev. Sci. Instr.}, volume = {58}, year = {1987}, pages = {632{\textendash}638}, author = {Bishop, G. A. and Parody-Morreale, A. and Robert, C. and and Gill, S. J.} } @inbook {1987|1429, title = {Nesting- An extension of the MWC model and its application to tarantula hemocyanin}, booktitle = {Invertebrate Oxygen Carriers}, year = {1987}, publisher = {Springer-Verlag}, organization = {Springer-Verlag}, address = {Berlin}, author = {Decker, H. and Robert, C. H. and Gill, S. J.} } @article {1987|1967, title = {Nesting: hierarchies of allosteric interactions}, journal = {Proc. Natl. Acad. Sci. U.s.a.}, volume = {84}, number = {7}, year = {1987}, month = {apr}, pages = {1891{\textendash}1895}, author = {Robert, C H and Decker, H and Richey, B and Gill, S J and Wyman, J} } @article {1987|1592, title = {Oxygen binding constants for human hemoglobin tetramers}, journal = {Biochemistry}, volume = {26}, number = {13}, year = {1987}, month = {jun}, pages = {3995{\textendash}4002}, author = {Gill, S J and Di Cera, E and Doyle, M L and Bishop, G A and Charles H. Robert} } @article {1986|1781, title = {Analysis of zeros of binding polynomials for tetrameric hemoglobins}, journal = {Biophys. Chem.}, volume = {24}, number = {3}, year = {1986}, month = {aug}, pages = {295{\textendash}309}, author = {Connelly, P R and Charles H. Robert and Briggs, W E and Gill, S J} } @article {1986|1602, title = {Cooperative free energies for nested allosteric models as applied to human hemoglobin}, journal = {Biophys. J.}, volume = {50}, number = {4}, year = {1986}, month = {oct}, pages = {747{\textendash}752}, author = {Gill, S J and Charles H. Robert and Coletta, M and Di Cera, E and Brunori, M} }