@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 {2019|2081, title = {Visualizing Biological Membrane Organization and Dynamics.}, journal = {J Mol Biol}, volume = {431}, year = {2019}, month = {2019 05 03}, pages = {1889-1919}, abstract = {

Biological membranes are fascinating. Santiago Ram{\'o}n y Cajal, who received the Nobel prize in 1906 together with Camillo Golgi for their work on the nervous system, wrote \"[\…]in the study of this membrane[\…] I felt more profoundly than in any other subject of study the shuddering sensation of the unfathomable mystery of life\". The visualization and conceptualization of these biological objects have profoundly shaped many aspects of modern biology, drawing inspiration from experiments, computer simulations, and the imagination of scientists and artists. The aim of this review is to provide a fresh look on current ideas of biological membrane organization and dynamics by discussing selected examples across fields.

}, keywords = {Animals, Cell Membrane, Humans, Lipid Bilayers, Microscopy, Atomic Force, Microscopy, Electron, Transmission, Molecular Dynamics Simulation}, issn = {1089-8638}, doi = {10.1016/j.jmb.2019.02.018}, author = {Marc Baaden} } @article {2018|2086, title = {Analyzing protein topology based on Laguerre tessellation of a pore-traversing water network.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 09 10}, pages = {13540}, abstract = {

Given the tight relation between protein structure and function, we present a set of methods to analyze protein topology, implemented in the VLDP program, relying on Laguerre space partitions built from series of molecular dynamics snapshots. The Laguerre partition specifies inter-atomic contacts, formalized in graphs. The deduced properties are the existence and count of water aggregates, possible passage ways and constrictions, the structure, connectivity, stability and depth of the water network. As a test-case, the membrane protein FepA is investigated in its full environment, yielding a more precise description of the protein surface. Inside FepA, the solvent splits into isolated clusters and an intricate network connecting both sides of the lipid bilayer. The network is dynamic, connections set on and off, occasionally substantially relocating traversing paths. Subtle differences are detected between two forms of FepA, ligand-free and complexed with its natural iron carrier, the enterobactin. The complexed form has more constricted and more centered openings in the upper part whereas, in the lower part, constriction is released: two main channels between the plug and barrel lead directly to the periplasm. Reliability, precision and the variety of topological features are the main interest of the method.

}, keywords = {Bacterial Outer Membrane Proteins, Carrier Proteins, Enterobactin, Molecular Dynamics Simulation, Protein Stability, Protein Structure, Secondary, Receptors, Cell Surface, Structure-Activity Relationship, Water}, issn = {2045-2322}, doi = {10.1038/s41598-018-31422-5}, author = {Esque, J{\'e}r{\'e}my and Sansom, Mark S P and Marc Baaden and Oguey, Christophe} } @article {2018|2094, title = {Holding the Nucleosome Together: A Quantitative Description of the DNA-Histone Interface in Solution.}, journal = {J Chem Theory Comput}, volume = {14}, year = {2018}, month = {2018 Feb 13}, pages = {1045-1058}, abstract = {

The nucleosome is the fundamental unit of eukaryotic genome packaging in the chromatin. In this complex, the DNA wraps around eight histone proteins to form a superhelical double helix. The resulting bending, stronger than anything observed in free DNA, raises the question of how such a distortion is stabilized by the proteic and solvent environments. In this work, the DNA-histone interface in solution was exhaustively analyzed from nucleosome structures generated by molecular dynamics. An original Voronoi tessellation technique, measuring the topology of interacting elements without any empirical or subjective adjustment, was used to characterize the interface in terms of contact area and occurrence. Our results revealed an interface more robust than previously known, combining extensive, long-lived nonelectrostatic and electrostatic interactions between DNA and both structured and unstructured histone regions. Cation accumulation makes the proximity of juxtaposed DNA gyres in the superhelix possible by shielding the strong electrostatic repulsion of the charged phosphate groups. Overall, this study provides new insights on the nucleosome cohesion, explaining how DNA distortions can be maintained in a nucleoprotein complex.

}, keywords = {DNA, Histones, Molecular Dynamics Simulation, Nucleosomes, Solutions, Static Electricity}, issn = {1549-9626}, doi = {10.1021/acs.jctc.7b00936}, author = {Elbahnsi, Ahmad and Retureau, Romain and Marc Baaden and Hartmann, Brigitte and Oguey, Christophe} } @article {2018|2087, title = {The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation .}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 07 19}, abstract = {

, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-β-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the β-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45\% stretching between the two α-helices linked by the site and a 15\% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating embryos. This is followed by the predicted release of 16\% of β-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the β-catenin pathway process.

}, keywords = {Amino Acid Sequence, Animals, Armadillo Domain Proteins, Binding Sites, Cadherins, Cell Differentiation, Drosophila melanogaster, Drosophila Proteins, Fluorescence Resonance Energy Transfer, Mechanotransduction, Cellular, Molecular Dynamics Simulation, Phosphorylation, Protein Binding, Protein Conformation, Proto-Oncogene Proteins pp60(c-src), Sequence Homology, Transcription Factors}, issn = {2050-084X}, doi = {10.7554/eLife.33381}, author = {R{\"o}per, Jens-Christian and Mitrossilis, D{\'e}mosth{\`e}ne and Guillaume Stirnemann and Waharte, Fran{\c c}ois and Brito, Isabel and Fernandez-Sanchez, Maria-Elena and Marc Baaden and Salamero, Jean and Farge, Emmanuel} } @article {2017|2095, title = {Residues of Alpha Helix H3 Determine Distinctive Features of Transforming Growth Factor β3.}, journal = {J Phys Chem B}, volume = {121}, year = {2017}, month = {2017 06 08}, pages = {5483-5498}, abstract = {

Transforming growth factors (TGF-βs) are proteins that regulate cell growth by binding to their receptors. In contrast to transforming growth factor (TGF) β1, TGF-β3 homodimer is believed to exist also in an open conformation, in which both of its monomers are loosely packed against each other. At the origin of this difference is the H3-helix. Its sequence and degree of structuration seem to govern the outcome of TGF dimerization. We docked two monomers of TGF-β3 with intact and altered H3 α-helix against each other using HADDOCK. TGF-β3 monomer with an intact H3-helix exclusively forms closed conformations of homodimer, whereas the open conformation may coexist with the closed one when a part of the H3 α-helix is destabilized. We quantify the difference in its conformational preference for the open versus the closed structure by calculating the binding energy between monomers using the MMPBSA approach. We compare the wild type (wt) TGFβ3/TGFβ1 homodimers in the Protein Data Bank to a swapped mutant where all residues of the H3-helix were mutated to the respective TGFβ1/TGFβ3 sequence. Swapping stabilizes the closed conformation and destabilizes the open conformation of TGFβ3. Further detailed insight is derived from molecular dynamics simulation studies suggesting that Val 61 of the H3-helix may act as an anchor residue for the closed conformation of TGFβ3. Computational alanine scanning mutagenesis confirms that several residues of the H3-helix are the hot residues for the closed conformation of TGFβ3. These observations may bear relevance to general conformational transitions in proteins and specifically in the TGFβ superfamily.

}, keywords = {Molecular Dynamics Simulation, Protein Conformation, alpha-Helical, Transforming Growth Factor beta3}, issn = {1520-5207}, doi = {10.1021/acs.jpcb.7b01867}, author = {Nayeem, Shahid M and Oteri, Francesco and Marc Baaden and Deep, Shashank} }