@article {2020|2131, title = {Tau R3-R4 Domain Dimer of the Wild Type and Phosphorylated Ser356 Sequences. I. In Solution by Atomistic Simulations.}, journal = {J Phys Chem B}, year = {2020}, month = {2020 Mar 27}, abstract = {

In Alzheimer\&$\#$39;s disease, neurofibrillary lesions correlate with cognitive deficits and consist of inclusions of tau protein with cross-β structure. A stable dimeric form of soluble tau has been evidenced in the cells, but its high-resolution structure is missing in solution. We know, however, that cryo-electron microscopy (c-EM) of full-length tau in the brain of an individual with AD displays a core of eight β-sheets with a C-shaped architecture spanning the R3-R4 repeat domain, while the rest of the protein is very flexible. To address the conformational ensemble of the dimer, we performed atomistic replica exchange molecular dynamics simulations on the tau R3-R4 domain starting from the c-EM configuration. We find that the wild type tau R3-R4 dimer explores elongated, U-shaped, V-shaped and globular forms rather than the C-shape. Phosphorylation of Ser356, pSer356, is known to block the interaction between the tau protein and the amyloid-β42 peptide. Standard molecular dynamics simulations of this phosphorylated sequence for a total of 5 microseconds compared to its wild type counterpart show a modulation of the population of β-helices and accessible topologies, and a decrease of intermediates near the fibril like conformers.

}, issn = {1520-5207}, doi = {10.1021/acs.jpcb.0c00574}, author = {Philippe Derreumaux and Man, Viet Hoang and Wang, Junmei and Phuong Hoang Nguyen} } @article {2019|2106, title = {Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. I. In a Bilayer Mimicking a Neuronal Membrane.}, journal = {J Phys Chem B}, volume = {123}, year = {2019}, month = {2019 May 02}, pages = {3643-3648}, abstract = {

The amyloid-β (Aβ) 42 oligomers are much more toxic than Aβ40 oligomers in Alzheimer\&$\#$39;s disease. Numerous experiments indicate that toxicity could involve the formation of pores in membranes, but experimental high-resolution structure determination of these pore-forming Aβ oligomers has been impeded by aggregate heterogeneity. Using extensive atomistic simulations, low-resolution data obtained in lipid bilayers, and other theoretical factors, we proposed atomic structures of Aβ40 and Aβ42 β-barrels in a bilayer mimicking a neuronal membrane. The 3D model, which consists of tetramer subunits, two distinct β-hairpin motifs and an asymmetric arrangement of eight antiparallel β-strands, is drastically destabilized for Aβ40 compared to its Aβ42 counterpart. Our computational modeling has several implications in Alzheimer\&$\#$39;s disease, sheds light on the amyloid pore hypothesis, and explains the higher deleterious property of Aβ42.

}, issn = {1520-5207}, doi = {10.1021/acs.jpcb.9b01206}, author = {Phuong Hoang Nguyen and Campanera, Josep M and Ngo, Son Tung and Loquet, Antoine and Philippe Derreumaux} } @article {2019|2105, title = {Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. II. In Aqueous Solution.}, journal = {J Phys Chem B}, volume = {123}, year = {2019}, month = {2019 Aug 08}, pages = {6750-6756}, abstract = {

Alzheimer\&$\#$39;s disease (AD) is characterized by the accumulation of extracellular Aβ42 and Aβ40 oligomers and plaques. In a recent computational study, we found that the presence of the residues I41 and A42 increases significantly the propensity of Aβ to form a tetrameric β-barrel structure in a bilayer mimicking a neuronal membrane. In this work, we have determined the propensity of the two Aβ proteins to form tetrameric β-barrel structures in aqueous solution using four atomistic protein fields, that is, Amber99SB-ILDN/TIP3P, OPLS/TIP3P, CHARMM36m/TIP3P-modified, and Amber99SB/DISP. Extensive replica exchange molecular dynamics simulations make it clear that a β-barrel, made of two distinct β-hairpin motifs and an asymmetric arrangement of eight antiparallel β-strands with an inner pore diameter of 0.7 nm, exists transiently for Aβ42 peptide, but this is less the case for Aβ40 peptide, due to the change of the CHC-CHC and the Cter-Cter interfaces. This study has several implications in AD.

}, issn = {1520-5207}, doi = {10.1021/acs.jpcb.9b05288}, author = {Phuong Hoang Nguyen and Campanera, Josep M and Ngo, Son Tung and Loquet, Antoine and Philippe Derreumaux} } @article {2018|2138, title = {Three Weaknesses for Three Perturbations: Comparing Protein Unfolding Under Shear, Force, and Thermal Stresses}, journal = {J Phys Chem B}, volume = {122}, year = {2018}, month = {Dec}, pages = {11922-11930}, abstract = {

The perturbation of a protein conformation by a physiological fluid flow is crucial in various biological processes including blood clotting and bacterial adhesion to human tissues. Investigating such mechanisms by computer simulations is thus of great interest, but it requires development of ad hoc strategies to mimic the complex hydrodynamic interactions acting on the protein from the surrounding flow. In this study, we apply the Lattice Boltzmann Molecular Dynamics (LBMD) technique built on the implicit solvent coarse-grained model for protein Optimized Potential for Efficient peptide structure Prediction (OPEP) and a mesoscopic representation of the fluid solvent, to simulate the unfolding of a small globular cold-shock protein in shear flow and to compare it to the unfolding mechanisms caused either by mechanical or thermal perturbations. We show that each perturbation probes a specific weakness of the protein and causes the disruption of the native fold along different unfolding pathways. Notably, the shear flow and the thermal unfolding exhibit very similar pathways, while because of the directionality of the perturbation, the unfolding under force is quite different. For force and thermal disruption of the native state, the coarse-grained simulations are compared to all-atom simulations in explicit solvent, showing an excellent agreement in the explored unfolding mechanisms. These findings encourage the use of LBMD based on the OPEP model to investigate how a flow can affect the function of larger proteins, for example, in catch-bond systems.

}, doi = {10.1021/acs.jpcb.8b08711}, author = {Languin-Catto{\"e}n, Olivier and Melchionna, Simone and Philippe Derreumaux and Guillaume Stirnemann and Sterpone, Fabio} } @conference {2016|1608, title = {Toward Microscopic Simulations of Proteins in Cell-Like Environments}, booktitle = {Biophys. J.}, volume = {110}, number = {3, 1}, year = {2016}, note = {60th Annual Meeting of the Biophysical-Society, Los Angeles, CA, FEB 27-MAR 02, 2016}, month = {feb}, pages = {386A}, publisher = {Biophys Soc}, organization = {Biophys Soc}, issn = {0006-3495}, author = {Fabio Sterpone and Philippe Derreumaux and Melchionna, Simone} } @article {2014|1905, title = {Theoretical study of the NLO responses of some natural and unnatural amino acids used as probe molecules}, journal = {J. Mol. Model.}, volume = {20}, number = {8}, year = {2014}, month = {aug}, pages = {2388}, doi = {10.1007/s00894-014-2388-0}, author = {Derrar, S. N. and Sekkal-Rahal, M. and Philippe Derreumaux and Springborg, M.} } @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 {2009|1986, title = {Targeting the early steps of A beta 16-22 protofibril disassembly by N-methylated inhibitors: A numerical study}, journal = {Proteins: Struct., Funct., Bioinf.}, volume = {75}, number = {2}, year = {2009}, month = {may}, pages = {442{\textendash}452}, doi = {10.1002/prot.22254}, author = {Y Chebaro and Philippe Derreumaux} } @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 {1994|1897, title = {A TRUNCATED NEWTON MINIMIZER ADAPTED FOR CHARMM AND BIOMOLECULAR APPLICATIONS}, journal = {J. Comput. Chem.}, volume = {15}, number = {5}, year = {1994}, month = {may}, pages = {532{\textendash}552}, doi = {10.1002/jcc.540150506}, author = {Philippe Derreumaux and ZHANG, GH and SCHLICK, T and BROOKS, B} }