Normand Mousseau

Paris Diderot University, Lutetia Parisorum, Île-de-France, France

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Publications (166)339.54 Total impact

  • Sébastien Côté, Guanghong Wei, Normand Mousseau
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    ABSTRACT: The huntingtin protein is characterized by a segment of consecutive glutamines (Q$_N$) that is responsible for its fibrillation. As with other amyloid proteins, misfolding of huntingtin is related to Huntington's disease through pathways that can involve interactions with phospholipid membranes. Experimental results suggest that the N-terminal 17-amino-acid sequence (htt$^{NT}$) positioned just before the Q$_N$ region is important for the binding of huntingtin to membranes. Through all-atom explicit solvent molecular dynamics simulations, we unveil the structure and dynamics of the htt$^{NT}$Q$_N$ fragment on a phospholipid membrane at the atomic level. We observe that the insertion dynamics of this peptide can be described by four main steps -- approach, reorganization, anchoring and insertion -- that are very diverse at the atomic level. On the membrane, the htt$^{NT}$ peptide forms a stable $\alpha$-helix essentially parallel to the membrane with its non-polar side-chains -- mainly Leu-4, Leu-7, Phe-11 and Leu-14 -- positioned in the hydrophobic core of the membrane. Salt-bridges involving Glu-5, Glu-12, Lys-6 and Lys-15, as well as hydrogen bonds involving Thr-3 and Ser-13 with the phospholipids also stabilize the structure and orientation of the htt$^{NT}$ peptide. These observations do not significantly change upon adding the Q$_N$ region whose role is rather to provide, through its hydrogen bonds with the phospholipids' head group, a stable scaffold facilitating the partitioning of the htt$^{NT}$ region in the membrane. Moreover, by staying accessible to the solvent, the amyloidogenic Q$_N$ region could also play a key role for the oligomerization of htt$^{NT}$Q$_N$ on phospholipid membranes. © Proteins 2014;. © 2014 Wiley Periodicals, Inc.
    Proteins Structure Function and Bioinformatics 01/2014; · 3.34 Impact Factor
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    ABSTRACT: We study ion-damaged crystalline silicon by combining nanocalorimetric experiments with an off-lattice kinetic Monte Carlo simulation to identify the atomistic mechanisms responsible for the structural relaxation over long time scales. We relate the logarithmic relaxation, observed in a number of disordered systems, with heat-release measurements. The microscopic mechanism associated with this logarithmic relaxation can be described as a two-step replenish and relax process. As the system relaxes, it reaches deeper energy states with logarithmically growing barriers that need to be unlocked to replenish the heat-releasing events leading to lower-energy configurations.
    Physical Review Letters 09/2013; 111(10). · 7.94 Impact Factor
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    ABSTRACT: The nature of structural relaxation in disordered systems such as amorphous silicon (a-Si) remains a fundamental issue in our attempts at understanding these materials. While a number of experiments suggest that mechanisms similar to those observed in crystals, such as vacancies, could dominate the relaxation, theoretical arguments point rather to the possibility of more diverse pathways. Using the kinetic activation-relaxation technique, an off-lattice kinetic Monte Carlo method with on-the-fly catalog construction, we resolve this question by following 1000 independent vacancies in a well-relaxed a-Si model at 300 K over a timescale of up to one second. Less than one percent of these survive over this period of time and none diffuse more than once, showing that relaxation and diffusion mechanisms in disordered systems are fundamentally different from those in the crystal.
    Physical review. B, Condensed matter 04/2013; 87(14).
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    ABSTRACT: Fatigue and aging of materials are, in large part, determined by the evolution of the atomic-scale structure in response to strains and perturbations. This coupling between microscopic structure and long time scales remains one of the main challenges in materials study. Focusing on a model system, ion-damaged crystalline silicon, we combine nanocalorimetric experiments with an off-lattice kinetic Monte Carlo simulation to identify the atomistic mechanisms responsible for the structural relaxation over long time scales. We relate the logarithmic relaxation, observed in a number of systems, with heat-release measurements. The microscopic mechanism associated with logarithmic relaxation can be described as a two-step replenish and relax process. As the system relaxes, it reaches deeper energy states with logarithmically growing barriers that need to be unlocked to replenish the heat-releasing events leading to lower energy configurations.
    04/2013;
  • Jean-Francois Joly, Normand Mousseau
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    ABSTRACT: The contribution of vacancy-like defects to the relaxation of amorphous silicon (a-Si) has been a matter of debate for a long time. Due to their disordered nature, there is a large number local environments in which such a defect can exists. Previous numerical studies the vacancy in a-Si have been limited to small systems and very short timescales. Here we use kinectic ART (k-ART), an off-lattice kinetic Monte-Carlo simulation method with on-the-fly catalog building [1,2] to study the time evolution of 1000 different single vacancy configurations in a well-relaxed a-Si model. Our results show that most of the vacancies are annihlated quickly. In fact, while 16% of the 1000 isolated vacancies survive for more than 1 ns of simulated time, 0.043% remain after 1 ms and only 6 of them survive longer than 0.1 second. Diffusion of the full vacancy is only seen in 19% of the configurations and diffusion usually leads directly to the annihilation of the defect. The actual annihilation event, in which one of the defective atoms fills the vacancy, is usually similar in all the configurations but local bonding environment heavily influence its activation barrier and relaxation energy. [4pt] [1] El-Mellouhi et al,Phys. Rev B. 78, (2008)[0pt] [2] Beland et al., Phys. Rev. E. 84, (2011)
    03/2013;
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    ABSTRACT: Because of the long-time scale involved, the activated diffusion of point defects is often studied in standard molecular dynamics at high temperatures only, making it more difficult to characterize complex diffusion mechanisms. Here, we turn to the study of point defect diffusion in crystalline silicon using kinetic ART (kART)[1-2], an off-lattice kinetic Monte Carlo method with on-the-fly catalog building based on the activation-relaxation technique (ART nouveau). By generating catalogs of diffusion mechanisms and fully incorporating elastic and off-lattice effects, kART is a unique tool for characterizing this problem. More precisely, using kART with the standard Stillinger-Weber potential we consider the evolution of crystalline cells with 1 to 4 vacancies and 1 to 4 interstitials at various temperatures and to provide a detailed picture of both the atomistic diffusion mechanisms and overall kinetics in addition to identifying special configurations such as a 2-interstitial super-diffuser. [4pt] [1] F. El-Mellouhi, N. Mousseau and L.J. Lewis, Phys. Rev. B. 78, 153202 (2008)[0pt] [2] L. K. Béland, P. Brommer, F. El-Mellouhi, J.-F. Joly and N. Mousseau, Phys. Rev. E 84, 046704 (2011).
    03/2013;
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    ABSTRACT: In the last two decades, there has been a considerable interest in the development of accelerated numerical methods for sampling the energy landscape of complex materials. Many of these methods are based on the kinetic Monte Carlo (KMC) algorithm introduced 40 years ago. This is the case of kinetic ART, for example, which uses a very efficient transition-state searching method, ART nouveau, coupled with a topological tool, NAUTY, to offer an off-lattice KMC method with on-the-fly catalog building to study complex systems, such as ion-bombarded and amorphous materials, on timescales of a second or more. Looking at two systems, vacancy aggregation in Fe and energy relaxation in ion-bombarded c-Si, we characterize the changes in the energy landscape and the relation to its time evolution with kinetic ART and its correspondence with the well-known Bell-Evans-Polanyi principle used in chemistry.
    03/2013;
  • J Nasica-Labouze, N Mousseau
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    ABSTRACT: Alzheimer's disease is the most common form of senile dementia, affecting more than 24 million people worldwide. It is characterised pathologically by abnormally high levels of neurofibrillary tangles resulting from the accumulation of tau protein in dead and dying neurons, and by elevated numbers of senile plaques in the cortex and hippocampus of the brain. The major component of senile plaques is a small protein of 39–43 amino acids called amyloid-β (Aβ). Thus far, no treatment has been shown to slow the progression of sporadic and familial Alzheimer's disease. A large body of evidence points, however, to the early Aβ-formed oligomers as the primary toxic species in Alzheimer's disease. A powerful strategy for developing pharmaceutical treatments against Alzheimer's is to elucidate the pathways of oligomer formation and determine the structures of the toxic aggregates. This book provides a panoramic view across recent in vitro and in vivo studies along with state-of-the-art computer simulations, designed to increase the readers' understanding of Aβ oligomerisation and fibril formation. At the same time, the book delves into the pathogenesis of familial and sporadic Alzheimer's disease at the atomic level of detail. Written by leading authors in their respective fields, this book will be valuable to all scientists working on Alzheimer's disease.
    01/2013; Imperial Press College.
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    Applied Physics Letters 12/2012; 101(25). · 3.79 Impact Factor
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    Jessica Nasica-Labouze, Normand Mousseau
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    ABSTRACT: The small amyloid-forming GNNQQNY fragment of the prion sequence has been the subject of extensive experimental and numerical studies over the last few years. Using unbiased molecular dynamics with the OPEP coarse-grained potential, we focus here on the onset of aggregation in a 20-mer system. With a total of 16.9 [Formula: see text] of simulations at 280 K and 300 K, we show that the GNNQQNY aggregation follows the classical nucleation theory (CNT) in that the number of monomers in the aggregate is a very reliable descriptor of aggregation. We find that the critical nucleus size in this finite-size system is between 4 and 5 monomers at 280 K and 5 and 6 at 300 K, in overall agreement with experiment. The kinetics of growth cannot be fully accounted for by the CNT, however. For example, we observe considerable rearrangements after the nucleus is formed, as the system attempts to optimize its organization. We also clearly identify two large families of structures that are selected at the onset of aggregation demonstrating the presence of well-defined polymorphism, a signature of amyloid growth, already in the 20-mer aggregate.
    PLoS Computational Biology 11/2012; 8(11):e1002782. · 4.87 Impact Factor
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    ABSTRACT: Magnetism in two dimensional atomic sheets has attracted considerable interest as its existence could allow the development of electronic and spintronic devices. The existence of magnetism is not sufficient for devices, however, as states must be addressable and modifiable through the application of an external drive. We show that defects in hexagonal boron nitride present a strong interplay between the N-N distance in the edge and the magnetic moments of the defects. By stress-induced geometry modifications, we change the ground state magnetic moment of the defects. This control is made possible by the triangular shape of the defects as well as the strong spin localisation in the magnetic state.
    Applied Physics Letters 09/2012; 101(13). · 3.79 Impact Factor
  • Sébastien Côté, Guanghong Wei, Normand Mousseau
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    ABSTRACT: Several neurodegenerative diseases are associated with the polyglutamine (polyQ) repeat disorder in which a segment of consecutive glutamines in the native protein is produced with too many glutamines. Huntington's disease, for example, is related to the misfolding of the Huntingtin protein which occurs when the polyQ segment has more than approximately 36 glutamines. Experimentally, it is known that the polyQ segment alone aggregates into β-rich conformations such as amyloid fibrils. Its aggregation is modulated by the number of glutamine residues as well as by the surrounding amino acid sequences such as the 17-amino-acid N-terminal fragment of Huntingtin which increases the aggregation rate. Little structural information is available, however, regarding the first steps of aggregation and the atomistic mechanisms of oligomerization are yet to be described. Following previous coarse-grained replica-exchange molecular dynamics simulations that show the spontaneous formation of a nanotube consisting of two intertwined antiparallel strands (Laghaei, R.; Mousseau, N. J. Chem. Phys.2010, 132, 165102), we study this configuration and some extensions of it using all-atom explicit solvent MD simulations. We compare two different lengths for the polyQ segment, 40 and 30 glutamines, and we investigate the impact of the Huntingtin N-terminal residues (htt(NT)). Our results show that the dimeric nanotubes can provide a building block for the formation of longer nanotubes (hexamers and octamers). These longer nanotubes are characterized by large β-sheet propensities and a small solvent exposure of the main-chain atoms. Moreover, the oligomerization between two nanotubes occurs through the formation of protein/protein H-bonds and can result in an elongation of the water-filled core. Our results also show that the htt(NT) enhances the structural stability of the β-rich seeds, suggesting a new mechanism by which it can increase the aggregation rate of the amyloidogenic polyQ sequence.
    The Journal of Physical Chemistry B 09/2012; 116(40):12168-79. · 3.61 Impact Factor
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    ABSTRACT: Using the art nouveau method, we study the initial stages of silicon oxide formation. After validating the method's parameters with the characterization of point defects diffusion mechanisms in pure Stillinger-Weber silicon, which allows us to recover some known results and to detail vacancy and self-interstitial diffusion paths, the method is applied onto a system composed of an oxygen layer deposited on a silicon substrate. We observe the oxygen atoms as they move rapidly into the substrate. From these art nouveau simulations, we extract the energy barriers of elementary mechanisms involving oxygen atoms and leading to the formation of an amorphouslike silicon oxide. We show that the kinetics of formation can be understood in terms of the energy barriers between various coordination environments.
    Physical review. B, Condensed matter 08/2012; 86(7).
  • Peter Brommer, Normand Mousseau
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    ABSTRACT: A Comment on the Letter by Yue Fan et al., Phys. Rev. Lett. 106, 125501 (2011). The authors of the Letter offer a reply.
    Physical Review Letters 05/2012; 108(21). · 7.94 Impact Factor
  • Jean-François St-Pierre, Normand Mousseau
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    ABSTRACT: We present an adaptation of the ART-nouveau energy surface sampling method to the problem of loop structure prediction. This method, previously used to study protein folding pathways and peptide aggregation, is well suited to the problem of sampling the conformation space of large loops by targeting probable folding pathways instead of sampling exhaustively that space. The number of sampled conformations needed by ART nouveau to find the global energy minimum for a loop was found to scale linearly with the sequence length of the loop for loops between 8 and about 20 amino acids. Considering the linear scaling dependence of the computation cost on the loop sequence length for sampling new conformations, we estimate the total computational cost of sampling larger loops to scale quadratically compared to the exponential scaling of exhaustive search methods.
    Proteins Structure Function and Bioinformatics 04/2012; 80(7):1883-94. · 3.34 Impact Factor
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    ABSTRACT: The ATP binding cassette (ABC) transporter family of proteins contains members involved in ATP-mediated import or export of ligands at the cell membrane. For the case of exporters, the translocation mechanism involves a large-scale conformational change that involves a clothespin-like motion from an inward-facing open state, able to bind ligands and adenosine triphosphate (ATP), to an outward-facing closed state. Our work focuses on SAV1866, a bacterial member of the ABC transporter family for which the structure is known for the closed state. To evaluate the ability of this protein to undergo conformational changes at physiological temperature, we first performed conventional molecular dynamics (MD) on the cocrystallized adenosine diphosphate (ADP)-bound structure and on a nucleotide-free structure. With this assessment of SAV1866's stability, conformational changes were induced by steered molecular dynamics (SMD), in which the nucleotide binding domains (NBD) were pushed apart, simulating the ATP hydrolysis energy expenditure. We found that the transmembrane domain is not easily perturbed by large-scale motions of the NBDs.
    The Journal of Physical Chemistry B 03/2012; 116(9):2934-42. · 3.61 Impact Factor
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    ABSTRACT: The Amyloid-beta protein is related to Alzheimer's disease and various experiments have shown that oligomers as small as the dimer are cytotoxic. Two alloforms are mainly produced: Aβ1-40 and Aβ1-42. They have very different oligomer distributions, and it was recently suggested, from experimental studies, that this variation may originate from structural differences in their dimer structures. Little structural information is available on the Aβ dimer, however, and to complement experimental observations, we simulated the folding of the wild-type Aβ1-40 and Aβ1-42 dimers as well as the mutated Aβ1-40(D23N) dimer using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics. The D23N variant impedes the salt-bridge formation between D23-K28 seen in the wild-type Aβ leading to very different fibrillation properties and final amyloid fibrils. Our results show that the Aβ1-42 dimer has a higher propensity than the Aβ1-40 dimer to form β-strands at the central hydrophobic core (residues 17-21) and at the C-terminal (residues 30-42), which are two segments crucial to the oligomerization of Aβ. The free energy landscape of the Aβ1-42 dimer is also broader and more complex than that of the Aβ1-40 dimer. Interestingly, D23N also impacts the free energy landscape by increasing the population of configurations with higher β-strand propensities when compared against Aβ1-40. In addition, while Aβ1-40(D23N) displays a higher β-strand propensity at the C-terminal, its solvent accessibility does not change with respect to the wild-type sequence. Overall, our results show the strong impact of the two amino acids Ile41-Ala42 and the salt-bridge D23-K28 on the folding of the Aβ dimer.
    The Journal of Physical Chemistry B 03/2012; · 3.61 Impact Factor
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    ABSTRACT: The amyloid-β protein (Aβ) oligomers are believed to be the main culprits in the cytoxicity of Alzheimer's disease (AD) and p3 peptides (Aβ17-42 fragments) are present in AD amyloid plaques. Many small-molecule or peptide-based inhibitors are known to slow down Aβ aggregation and reduce the toxicity in vitro, but their exact modes of action remain to be determined since there has been no atomic level of Aβ(p3)-drug oligomers. In this study, we have determined the structure of Aβ17-42 trimers both in aqueous solution and in the presence of five small-molecule inhibitors using a multiscale computational study. These inhibitors include 2002-H20, curcumin, EGCG, Nqtrp, and resveratrol. First, we used replica exchange molecular dynamics simulations coupled to the coarse-grained (CG) OPEP force field. These CG simulations reveal that the conformational ensemble of Aβ17-42 trimer can be described by 14 clusters with each peptide essentially adopting turn/random coil configurations, although the most populated cluster is characterized by one peptide with a β-hairpin at Phe19-Leu31. Second, these 14 dominant clusters and the less-frequent fibril-like state with parallel register of the peptides were subjected to atomistic Autodock simulations. Our analysis reveals that the drugs have multiple binding modes with different binding affinities for trimeric Aβ17-42 although they interact preferentially with the CHC region (residues 17-21). The compounds 2002-H20 and Nqtrp are found to be the worst and best binders, respectively, suggesting that the drugs may interfere at different stages of Aβ oligomerization. Finally, explicit solvent molecular dynamics of two predicted Nqtrp-Aβ17-42 conformations describe at atomic level some possible modes of action for Nqtrp.
    The Journal of Physical Chemistry B 02/2012; 116(29):8412-22. · 3.61 Impact Factor
  • Peter Brommer, Normand Mousseau
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    ABSTRACT: Defects in metals are challenging to study in linear simulation schemes like molecular dynamics (MD), as diffusive activation barriers are typically high compared to kBT, and most ressources are devoted to integrating out thermal vibration. Simultaneously, low-energy non-diffusive rearrangements (so-called basins) are serious obstacles for methods that use state-to-state trajectories like kinetic Monte Carlo (KMC). We combined the kinetic Activation-Relaxation technique (k-ART, [1]), an off-lattice, self-learning KMC method which correctly reproduces long-range interactions, with an autonomous basin identification scheme that averages over all in-basin transitions. This allows us to study defect evolution on much longer time scales than MD. In this talk, we present results on the vacancy cluster formation in bcc iron and interface diffusion in the Cu--Zr system.[4pt] [1] B'eland, Brommer, et al., Phys. Rev. E, 84, 046704 (2011).
    02/2012;
  • Jean-Francois Joly, Normand Mousseau
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    ABSTRACT: Hydrogenated amorphous silicon (a-Si:H) is an important semiconducting material used in many applications from solar cells to transistors. In 2010, Houssem et al. [1], using the open-ended saddle-point search method, ART nouveau, studied the characteristics of the potential energy landscape of a-Si as a function of relaxation. Here, we extend this study and follow the impact of hydrogen doping on the same a-Si models as a function of doping level. Hydrogen atoms are first attached to dangling bonds, then are positioned to relieve strained bonds of fivefold coordinated silicon atoms. Once these sites are saturated, further doping is achieved with a Monte-Carlo bond switching method that preserves coordination and reduces stress [2]. Bonded interactions are described with a modified Stillinger-Weber potential and non-bonded Si-H and H-H interactions with an adapted Slater-Buckingham potential. Large series of ART nouveau searches are initiated on each model, resulting in an extended catalogue of events that characterize the evolution of potential energy surface as a function of H-doping. [4pt] [1] Houssem et al., Phys Rev. Lett., 105, 045503 (2010)[0pt] [2] Mousseau et al., Phys Rev. B, 41, 3702 (1990)
    02/2012;

Publication Stats

1k Citations
339.54 Total Impact Points

Institutions

  • 2004–2012
    • Paris Diderot University
      • Laboratoire de Biochimie Théorique (LBT) UPR 9080
      Lutetia Parisorum, Île-de-France, France
    • Optech Montréal
      Montréal, Quebec, Canada
  • 2002–2012
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1990–2012
    • Université de Montréal
      Montréal, Quebec, Canada
  • 2007–2011
    • Fudan University
      • Department of Physics
      Shanghai, Shanghai Shi, China
  • 2006–2009
    • Institute of Physical and Chemical Biology
      Lutetia Parisorum, Île-de-France, France
  • 2004–2007
    • French National Centre for Scientific Research
      • Institut de Biologie Physico-Chimique
      Lyon, Rhone-Alpes, France
  • 2001–2006
    • Universiteit Utrecht
      • Institute for Theoretical Physics
      Utrecht, Provincie Utrecht, Netherlands
  • 2003
    • University of Cambridge
      • Department of Chemistry
      Cambridge, ENG, United Kingdom
  • 1998–2003
    • Ohio University
      • Department of Physics and Astronomy
      Athens, Ohio, United States
  • 1996–1997
    • Delft University of Technology
      Delft, South Holland, Netherlands
    • University of Oxford
      Oxford, England, United Kingdom
  • 1992–1995
    • Michigan State University
      • Department of Physics and Astronomy
      East Lansing, Michigan, United States