@article {2021|2146, title = {When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes}, journal = {Biomolecules}, volume = {11}, year = {2021}, pages = {1529}, abstract = {

The degree of proteins structural organization ranges from highly structured, compact folding to intrinsic disorder, where each degree of self-organization corresponds to specific functions: well-organized structural motifs in enzymes offer a proper environment for precisely positioned functional groups to participate in catalytic reactions; at the other end of the self-organization spectrum, intrinsically disordered proteins act as binding hubs via the formation of multiple, transient and often non-specific interactions. This review focusses on cases where structurally organized proteins or domains associate with highly disordered protein chains, leading to the formation of interfaces with varying degrees of fuzziness. We present a review of the computational methods developed to provide us with information on such fuzzy interfaces, and how they integrate experimental information. The discussion focusses on two specific cases, microtubules and homologous recombination nucleoprotein filaments, where a network of intrinsically disordered tails exerts regulatory function in recruiting partner macromolecules, proteins or DNA and tuning the atomic level association. Notably, we show how computational approaches such as molecular dynamics simulations can bring new knowledge to help bridging the gap between experimental analysis, that mostly concerns ensemble properties, and the behavior of individual disordered protein chains that contribute to regulation functions.

}, issn = {2218-273X}, doi = {10.3390/biom11101529}, url = {https://www.mdpi.com/2218-273X/11/10/1529}, author = {S Sacquin-Mora and Chantal Pr{\'e}vost} } @article {2020|2141, title = {Water dynamics at electrified graphene interfaces: a jump model perspective}, journal = {Phys Chem Chem Phys}, year = {2020}, month = {Mar}, abstract = {

The reorientation dynamics of water at electrified graphene interfaces was recently shown [J. Phys. Chem. Lett., 2020, 11, 624-631] to exhibit a surprising and strongly asymmetric behavior: positive electrode potentials slow down interfacial water reorientation, while for increasingly negative potentials water dynamics first accelerates before reaching an extremum and then being retarded for larger potentials. Here we use classical molecular dynamics simulations to determine the molecular mechanisms governing water dynamics at electrified interfaces. We show that changes in water reorientation dynamics with electrode potential arise from the electrified interfaces\&$\#$39; impacts on water hydrogen-bond jump exchanges, and can be quantitatively described by the extended jump model. Finally, our simulations indicate that no significant dynamical heterogeneity occurs within the water interfacial layer next to the weakly interacting graphene electrode.

}, doi = {10.1039/d0cp00359j}, author = {Zhang, Yiwei and Guillaume Stirnemann and Hynes, James T and Laage, Damien} } @article {2019|2065, title = {Weaving DNA strands: structural insight on ATP hydrolysis in RecA-induced homologous recombination}, journal = {Nucleic Acids Res}, volume = {47}, year = {2019}, month = {Sep}, pages = {7798-7808}, abstract = {

Homologous recombination is a fundamental process in all living organisms that allows the faithful repair of DNA double strand breaks, through the exchange of DNA strands between homologous regions of the genome. Results of three decades of investigation and recent fruitful observations have unveiled key elements of the reaction mechanism, which proceeds along nucleofilaments of recombinase proteins of the RecA family. Yet, one essential aspect of homologous recombination has largely been overlooked when deciphering the mechanism: while ATP is hydrolyzed in large quantity during the process, how exactly hydrolysis influences the DNA strand exchange reaction at the structural level remains to be elucidated. In this study, we build on a previous geometrical approach that studied the RecA filament variability without bound DNA to examine the putative implication of ATP hydrolysis on the structure, position, and interactions of up to three DNA strands within the RecA nucleofilament. Simulation results on modeled intermediates in the ATP cycle bring important clues about how local distortions in the DNA strand geometries resulting from ATP hydrolysis can aid sequence recognition by promoting local melting of already formed DNA heteroduplex and transient reverse strand exchange in a weaving type of mechanism.

}, doi = {10.1093/nar/gkz667}, author = {Boyer, Benjamin and Danilowicz, Claudia and Prentiss, Mara and Chantal Pr{\'e}vost} } @article {2018|2133, title = {Water dynamics in concentrated electrolytes: Local ion effect on hydrogen-bond jumps rather than collective coupling to ion clusters}, journal = {Proc Natl Acad Sci U S A}, volume = {115}, year = {2018}, month = {05}, pages = {E4953-E4954}, doi = {10.1073/pnas.1803988115}, author = {Guillaume Stirnemann and Jungwirth, Pavel and Laage, Damien} } @article {2018|2090, title = {Water permeation across artificial I-quartet membrane channels: from structure to disorder.}, journal = {Faraday Discuss}, volume = {209}, year = {2018}, month = {2018 09 28}, pages = {125-148}, abstract = {

Artificial water channels (AWCs) have been designed for water transport across membranes with the aim to mimic the high water permeability observed for biological systems such as aquaporins (\∼108-109 water molecules per s per channel), as well as their selectivity to reject ion permeation at the same time. Recent works on designed self-assembling alkylureido-ethylimidazole compounds forming imidazole-quartet channels (I-quartets), have shown both high water permeability and total ionic-rejection. I-quartets are thus promising candidates for further development of AWCs. However, the molecular mechanism of water permeation as well as I-quartet organization and stability in a membrane environment need to be fully understood to guide their optimal design. Here, we use a wide range of all-atom molecular dynamics (MD) simulations and their analysis to understand the structure/activity relationships of the I-quartet channels. Four different types with varying alkyl chain length or chirality have been studied in a complex fully hydrated lipid bilayer environment at both microsecond and nanosecond scale. Microsecond simulations show two distinct behaviors; (i) two out of four systems maintain chiral dipolar oriented water wires, but also undergo a strong reorganization of the crystal shape, (ii) the two other I-quartet channels completely lose the initial organization, nonetheless keeping a water transport activity. Short MD simulations with higher time resolution were conducted to characterize the dynamic properties of water molecules in these model channels and provided a detailed hypothesis on the molecular mechanism of water permeation. The ordered confined water was characterized with quantitative measures of hydrogen-bond life-time and single particle dynamics, showing variability among I-quartet channels. We will further discuss the underlying assumptions, currently based on self-aggregation simulations and crystal patches embedded in lipid bilayer simulations and attempt to describe possible alternative approaches to computationally capture the water permeation mechanism and the self-assembly process of these AWCs.

}, issn = {1364-5498}, doi = {10.1039/c8fd00046h}, author = {Murail, Samuel and Vasiliu, Tudor and Neamtu, Andrei and Barboiu, Mihail and Sterpone, Fabio and Marc Baaden} } @article {2017|2043, title = {Weak nanoscale chaos and anomalous relaxation in DNA}, journal = {Phys. Rev. E}, volume = {95}, year = {2017}, pages = {062417}, doi = {https://doi.org/10.1103/PhysRevE.95.062417}, author = {Alexey K. Mazur} } @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 {2017|2030, title = {Why Is Research on Amyloid-β Failing to Give New Drugs for Alzheimer{\textquoteright}s Disease?}, journal = {ACS Chem Neurosci}, volume = {8}, year = {2017}, month = {2017 Jul 19}, pages = {1435-1437}, abstract = {

The two hallmarks of Alzheimer\&$\#$39;s disease (AD) are the presence of neurofibrillary tangles (NFT) made of aggregates of the hyperphosphorylated tau protein and of amyloid plaques composed of amyloid-β (Aβ) peptides, primarily Aβ1-40 and Aβ1-42. Targeting the production, aggregation, and toxicity of Aβ with small molecule drugs or antibodies is an active area of AD research due to the general acceptance of the amyloid cascade hypothesis, but thus far all drugs targeting Aβ have failed. From a review of the recent literature and our own experience based on in vitro, in silico, and in vivo studies, we present some reasons to explain this repetitive failure.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Animals, Drug Discovery, Humans, Neuroprotective Agents}, issn = {1948-7193}, doi = {10.1021/acschemneuro.7b00188}, author = {Doig, Andrew J and Del Castillo-Frias, Maria P and Berthoumieu, Olivia and Tarus, Bogdan and Nasica-Labouze, Jessica and Sterpone, Fabio and Phuong Hoang Nguyen and Hooper, Nigel M and Faller, Peter and Philippe Derreumaux} } @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} } @conference {2015|1609, title = {What Computational Methods can Teach us about the Alzheimer-Protective Nature of A2V-and A2T-Mutant Amyloid-Beta Oligomers}, booktitle = {Biophys. J.}, volume = {108}, number = {2}, year = {2015}, pages = {204A-204A}, author = {Nasica-Labouze, Jessica and Tarus, Bogdan and Phuong Hoang Nguyen and Philippe Derreumaux} } @conference {2014|1783, title = {Wide Exploration of OPEP Protein Energy Landscapes using Advanced Monte Carlo Methods}, booktitle = {Biophys. J.}, volume = {106}, number = {2, 1}, year = {2014}, note = {58th Annual Meeting of the Biophysical-Society, San Francisco, CA, FEB 15-19, 2014}, month = {jan}, pages = {256A}, author = {Cragnolini, Tristan and Sutherland-Cash, Kyle H. and Wales, David and Pasquali, Samuela and Philippe Derreumaux} } @article {2013|1689, title = {When Does Trimethylamine N-Oxide Fold a Polymer Chain and Urea Unfold It?}, journal = {J. Phys. Chem. B}, volume = {117}, year = {2013}, pages = {8723{\textendash}8732}, abstract = {

Longstanding mechanistic questions about the role of protecting osmolyte trimethylamine N-oxide (TMAO) that favors protein folding and the denaturing osmolyte urea are addressed by studying their effects on the folding of uncharged polymer chains. Using atomistic molecular dynamics simulations, we show that 1 M TMAO and 7 M urea solutions act dramatically differently on these model polymer chains. Their behaviors are sensitive to the strength of the attractive dispersion interactions of the chain with its environment: when these dispersion interactions are sufficiently strong, TMAO suppresses the formation of extended conformations of the hydrophobic polymer as compared to water while urea promotes the formation of extended conformations. Similar trends are observed experimentally for real protein systems. Quite surprisingly, we find that both protecting and denaturing osmolytes strongly interact with the polymer, seemingly in contrast with existing explanations of the osmolyte effect on proteins. We show that what really matters for a protective osmolyte is its effective depletion as the polymer conformation changes, which leads to a negative change in the preferential binding coefficient. For TMAO, there is a much more favorable free energy of insertion of a single osmolyte near collapsed conformations of the polymer than near extended conformations. By contrast, urea is preferentially stabilized next to the extended conformation and thus has a denaturing effect.

}, isbn = {15206106}, url = {http://pubs.acs.org/doi/abs/10.1021/jp405609j$\backslash$nhttp://pubs.acs.org/doi/pdf/10.1021/jp405609j$\backslash$nhttp://dx.doi.org/10.1021/jp405609j}, author = {Mondal, Jagannath and Guillaume Stirnemann and Berne, B J} } @article {2012|1684, title = {Water jump reorientation and ultrafast vibrational spectroscopy}, journal = {J. Photochem. Photobiol. A}, volume = {234}, year = {2012}, pages = {75{\textendash}82}, abstract = {

The reorganization of water{\textquoteright}s hydrogen-bond (HB) network by breaking and making HBs lies at the heart of many of the pure liquid{\textquoteright}s special features and many aqueous media phenomena, including chemical reactions, ion transport and protein activity. An essential role in this reorganization is played by water molecule reorientation, long described by very small angular displacement Debye rotational diffusion. A markedly contrasting picture has been recently proposed, based on simulation and analytic modeling: a sudden, large amplitude jump mechanism, in which the reorienting water molecule rapidly exchanges HB partners in an activated process which has all the hallmarks of a chemical reaction. In this contribution, we offer a brief review of the jump mechanism together with a discussion of its application to, and probing by, modern ultrafast infrared spectroscopy experiments. Special emphasis is given to the direct characterization of the jumps via pioneering two-dimensional infrared spectroscopic measurements. ?? 2012 Elsevier B.V. All rights reserved.

}, keywords = {Hydrogen-bond dynamics, Pump-probe infrared spectroscopy, Two-dimensional infrared spectroscopy, Water dynamics}, issn = {10106030}, author = {Laage, Damien and Guillaume Stirnemann and Hynes, James T.} } @article {2012, title = {Water Jump Reorientation: From Theoretical Prediction to Experimental Observation}, journal = {Acc. Chem. Res.}, volume = {45}, number = {1}, year = {2012}, pages = {53{\textendash}62}, doi = {10.1021/ar200075u}, author = {Laage, Damien and Guillaume Stirnemann and Sterpone, Fabio and Hynes, James T.} } @article {2011|1739, title = {Water reorientation dynamics in the first hydration shells of F- and I-}, journal = {Phys. Chem. Chem. Phys.}, volume = {13}, year = {2011}, pages = {19895}, abstract = {

Molecular dynamics and analytic theory results are presented for the reorientation dynamics of first hydration shell water molecules around fluoride and iodide anions. These ions represent the extremes of the (normal) halide series in terms of their size and conventional structure-making and -breaking categorizations. The simulated reorientation times are consistent with NMR and ultrafast IR experimental results. They are also in good agreement with the theoretical predictions of the analytic Extended Jump Model. Analysis through this model shows that while sudden, large amplitude jumps (in which the reorienting water exchanges hydrogen-bond partners) are the dominant reorientation pathway for the I(-) case, they are comparatively less important for the F(-) case. In particular, the diffusive reorientation of an intact F(-)...H(2)O hydrogen-bonded pair is found to be most important for the reorientation time, a feature related to the greater hydrogen-bond strength for the F(-)...H(2)O pair. The dominance of this effect for e.g. multiply charged ions is suggested.

}, issn = {1463-9076}, author = {Boisson, Jean and Guillaume Stirnemann and Laage, Damien and Hynes, James T.} } @article {2010|1445, title = {Water around thermophilic proteins: the role of charged and apolar atoms}, journal = {J Phys: Cond Matt}, volume = {22}, number = {28}, year = {2010}, pages = {284113}, author = {Fabio Sterpone and Claudia Bertonati and Giuseppe Briganti and Simone Melchionna} } @article {2010|1692, title = {Water hydrogen bond dynamics in aqueous solutions of amphiphiles}, journal = {J. Phys. Chem. B}, volume = {114}, year = {2010}, pages = {3052{\textendash}3059}, abstract = {

The hydrogen bond dynamics of water in a series of amphiphilic solute solutions are investigated through simulations and analytic modeling with an emphasis on the interpretation of experimentally accessible two-dimensional infrared (2D IR) photon echo spectra. We evidence that for most solutes the major effect in the hydration dynamics comes from the hydrophilic groups. These groups can retard the water dynamics much more significantly than can hydrophobic groups by forming strong hydrogen bonds with water. By contrast, hydrophobic groups are shown to have a very moderate effect on water hydrogen bond breaking kinetics. We also present the first calculation of the 2D IR spectra for these solutions. While 2D IR spectroscopy is a powerful technique to probe water hydrogen bond network fluctuations, interpretations of aqueous solution spectra remain ambiguous. We show that a complementary approach through simulations and calculation of the spectra lifts the ambiguity and provides a clear connection between the simulated molecular picture and the experimental spectroscopy data. For amphiphilic solute solutions, we show that, in contrast with techniques such as NMR or ultrafast anisotropy, 2D IR spectroscopy can discriminate between waters next to the solutes hydrophobic and hydrophilic groups. We also evidence that the water dynamics slowdown due to the hydrophilic groups is dramatically enhanced in the 2D IR spectral relaxation, because these groups can induce a slow chemical exchange with the bulk, even when recognized exchange signatures are absent. Implications for the understanding of water around chemically heterogeneous systems such as protein surfaces and for the interpretation of 2D IR spectra in these cases are discussed.

}, issn = {15206106}, author = {Guillaume Stirnemann and Hynes, James T. and Laage, Damien} } @article {2010|1832, title = {Water hydrogen-bond dynamics around amino acids: the key role of hydrophilic hydrogen-bond acceptor groups}, journal = {J. Phys. Chem. B}, volume = {114}, number = {5}, year = {2010}, pages = {2083{\textendash}9}, abstract = {

Water hydrogen-bond (HB) dynamics around amino acids in dilute aqueous solution is investigated through molecular dynamics simulations and analytic modeling. We especially highlight the critical role played by hydrophilic HB acceptors: the strength of the HB formed with water has a pronounced effect on the HB dynamics, in accord with several experimental observations. In contrast, we evidence that hydrophilic HB donors induce a moderate slowdown in the water HB exchange dynamics due to an excluded volume effect, similar to that of hydrophobic groups. We present an analytic model which rationalizes the effect of all examined amino acid sites on the HB dynamics and whose predictions are in excellent agreement with the numerical simulations. This model provides the acceleration or retardation in the HB exchange time with respect to the bulk through the combination of the solute excluded volume factor with the solute-water HB strength factor, both referring to the HB exchange transition state.

}, author = {Sterpone, Fabio and Guillaume Stirnemann and Hynes, James T and Laage, Damien} } @article {2010|1649, title = {Water reorientation, hydrogen-bond dynamics and 2D-IR spectroscopy next to an extended hydrophobic surface.}, journal = {Farad. Discuss.}, volume = {146}, year = {2010}, pages = {263{\textendash}281}, abstract = {

The dynamics of water next to hydrophobic groups is critical for several fundamental biochemical processes such as protein folding and amyloid fiber aggregation. Some biomolecular systems, like melittin or other membrane-associated proteins, exhibit extended hydrophobic surfaces. Due to the strain these surfaces impose on the hydrogen (H)-bond network, the water molecules shift from the clathrate-like arrangement observed around small solutes to an anticlathrate-like geometry with some dangling OH bonds pointing toward the surface. Here we examine the water reorientation dynamics next to a model hydrophobic surface through molecular dynamics simulations and analytic modeling. We show that the water OH bonds lying next to the hydrophobic surface fall into two subensembles with distinct dynamical reorientation properties. The first is the OH bonds tangent to the surface; these exhibit a behavior similar to the water OHs around small hydrophobic solutes, i.e. with a moderate reorientational slowdown explained by an excluded volume effect due to the surface. The second is the dangling OHs pointing toward the surface: these are not engaged in any H-bond, reorient much faster than in the bulk, and exhibit an unusual anisotropy decay which becomes negative for delays of a few picoseconds. The H-bond dynamics, i.e. the exchanges between the different configurations, and the resulting anisotropy decays are analyzed within the analytic extended jump model. We also show that a recent spectroscopy technique, two-dimensional time resolved vibrational spectroscopy (2D-IR), can be used to selectively follow the dynamics of dangling OHs, since these are spectrally distinct from H-bonded ones. By computing the first 2D-IR spectra of water next to a hydrophobic surface, we establish a connection between the spectral dynamics and the dynamical properties that we obtain directly from the simulations.

}, issn = {1359-6640}, author = {Guillaume Stirnemann and Rossky, Peter J and Hynes, James T and Laage, Damien} } @article {2009|1693, title = {Why water reorientation slows without iceberg formation around hydrophobic solutes}, journal = {J. Phys. Chem. B}, volume = {113}, year = {2009}, pages = {2428{\textendash}2435}, abstract = {

The dynamics of water molecules next to hydrophobic solutes is investigated, specifically addressing the recent controversy raised by the first time-resolved observations, which concluded that some water molecules are immobilized by hydrophobic groups, in strong contrast to previous NMR conclusions. Through molecular dynamics simulations and an analytic jump reorientation model, we identify the water reorientation mechanism next to a hydrophobic solute and provide evidence that no water molecules are immobilized by hydrophobic solutes. Their moderate rotational slowdown compared to bulk water (e.g., by a factor of less than 2 at low solute concentration) is mainly due to slower hydrogen-bond exchange. The slowdown is quantitatively described by a solute excluded volume effect at the transition state for the key hydrogen-bond exchange in the reorientation mechanism. We show that this picture is consistent with both ultrafast anisotropy and NMR experimental results and that the transition state excluded volume theory yields quantitative predictions of the rotational slowdown for diverse hydrophobic solutes of varying size over a wide concentration range. We also explain why hydrophobic groups slow water reorientation less than do some hydrophilic groups.

}, author = {Laage, Damien and Guillaume Stirnemann and Hynes, James T.} } @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} } @article {2007|1861, title = {Water clustering and percolation in low hydration DNA shells}, journal = {J. Phys. Chem. B}, volume = {111}, number = {12}, year = {2007}, pages = {3258{\textendash}3266}, author = {Ivan Brovchenko and Aliaksei Krukau and Alla Oleinikova and Alexey K Mazur} } @article {2007|1949, title = {Wormlike chain theory and bending of short DNA}, journal = {Phys. Rev. Lett.}, volume = {98}, number = {21}, year = {2007}, pages = {218102}, author = {Alexey K Mazur} } @article {2006|1948, title = {Water percolation governs polymorphic transitions and conductivity of DNA}, journal = {Phys. Rev. Lett.}, volume = {97}, number = {13}, year = {2006}, pages = {137801}, author = {Ivan Brovchenko and Aliaksei Krukau and Alla Oleinikova and Alexey K Mazur} } @article {2002|1817, title = {Water rotational relaxation and diffusion in hydrated lysozyme}, journal = {J. Am. Chem. Soc.}, volume = {124}, number = {23}, year = {2002}, month = {jun}, pages = {6787{\textendash}91}, abstract = {This paper is concerned with the dynamics of water around a small globular protein. Dipolar second-rank relaxation time and diffusion properties of surface water were computed by extensive molecular dynamics simulations of lysozyme in water which lasted a total of 28 ns. Our results indicate that the rotational relaxation of water in the vicinity of lysozyme is 3-7 times slower than that in the bulk depending on how the hydration shell is defined in the calculation. We have also verified that the dynamics of water translational diffusion in the vicinity of lysozyme have retardations similar to rotational relaxation. This is a common assumption in nuclear magnetic relaxation dispersion (NMRD) studies to derive residence times. In contrast to bulk water dynamics, surface water is in a dispersive diffusion regime or subdiffusion. Very good agreement of dipolar second-rank relaxation time with NMRD estimates is obtained by using appropriate dimensions of the hydration shell. Although our computed second-rank dipolar retardations are independent of the water model, SPC/E describes more realistically the time scale of the water dynamics around lysozyme than does TIP3P.}, author = {Marchi, Massimo and Sterpone, Fabio and Ceccarelli, Matteo} }