Biomedical subjects

Normand Mousseau

Publications and source records attributed to Normand Mousseau.

15 recordsLinked to original sources

PubMed2007

Coarse-grained protein molecular dynamics simulations.

A limiting factor in biological science is the time-scale gap between experimental and computational trajectories. At this point, all-atom explicit solvent molecular dynamics (MD) are clearly too expensive to explore long-range protein motions and extract accurate thermodynamics of proteins in isolated or multimeric forms. To reach the appropriate time scale, we must then resort to coarse graining. Here we couple the coarse-grained OPEP model, which has already been used with activated methods, to MD simulations. Two test cases are studied: the stability of three proteins around their experimental structures and the aggregation mechanisms of the Alzheimer's Abeta16-22 peptides. We find that coarse-grained isolated proteins are stable at room temperature within 50 ns time scale. Based on two 220 ns trajectories starting from disordered chains, we find that four Abeta16-22 peptides can form a three-stranded beta sheet. We also demonstrate that the reptation move of one chain over the others, first observed using the activation-relaxation technique, is a kinetically important mechanism during aggregation. These results show that MD-OPEP is a particularly appropriate tool to study qualitatively the dynamics of long biological processes and the thermodynamics of molecular assemblies.

Amyloid beta-Peptides↗

PubMed2006

Aggregating the amyloid Abeta(11-25) peptide into a four-stranded beta-sheet structure.

We present a detailed analysis of the structural properties of one monomer of Abeta(11-25) as well as of the aggregation mechanisms for four chains of Abeta(11-25) using the activation-relaxation technique coupled with a generic energy potential. Starting from a random distribution of these four chains, we find that the system assembles rapidly into a random globular state that evolves into three- and four-stranded antiparallel beta-sheets. The aggregation process is considerably accelerated by the presence of preformed dimers. We also find that the reptation mechanism already identified in shorter peptides plays a significant role here in allowing the structure to reorganize without having to fully dissociate.

Amino Acid Sequence↗

PubMed2006

Structures of soluble amyloid oligomers from computer simulations.

Alzheimer's, Parkinson's, and Creutzfeldt-Jakob's neurodegenerative diseases are all linked with the assembly of normally soluble proteins into amyloid fibrils. Because of experimental limitations, structural characterization of the soluble oligomers, which form early in the process of fibrillogenesis and are cytotoxic, remains to be determined. In this article, we study the aggregation paths of seven chains of the shortest amyloid-forming peptide, using an activitated method and a reduced atomic representation. Our simulations show that disordered KFFE monomers ultimately form three distinct topologies of similar energy: amorphous oligomers, incomplete rings with beta-barrel character, and cross-beta-sheet structures with the meridional but not the equatorial X-ray fiber reflections. The simulations also shed light on the pathways from misfolded aggregates to fibrillar-like structures. They also underline the multiplicity of building blocks that can lead to the formation of the critical nucleus from which rapid growth of the fibril occurs.

Amyloid↗

PubMed2006

The conformations of the amyloid-beta (21-30) fragment can be described by three families in solution.

Alzheimer's disease has been linked to the self-assembly of the amyloid-beta protein of 40 and 42 residues. Although monomers are in equilibrium with higher-order species ranging from dimers to heptamers, structural knowledge of the monomeric amyloid-beta (Abeta) peptides is an important issue. Recent experimental data have shown that the fragment (21-30) is protease-resistant within full-length Abeta peptides and displays two structural families in solution. Because the details of the Abeta(21-30) structures found using distinct force fields and protocols differ at various degrees from those of the NMR structures, we revisit the conformational space of this peptide using the activation-relaxation technique (ART nouveau) coupled with a coarse-grained force field (OPEP v.3.0). We find that although Abeta(21-30) does not have a secondary structure, it dominantly populates three structural families, with a loop spanning residues Val24-Lys28. The first two families, which differ in the nature of the electrostatic interactions, satisfy the five interproton rotating frame nuclear Overhauser effect spectroscopy (ROESY) distances and superpose well onto the NMR structures. The third family, which cannot be seen by ROESY NMR experiments, displays a more open structure. This numeric study complements the experimental results by providing a much more detailed description of the dominant structures. Moreover, it provides further evidence of the capability of ART OPEP in providing a reliable conformational picture of peptides in solution.

Amyloid beta-Peptides↗

PubMed2006

Self-organization with equilibration: a model for the intermediate phase in rigidity percolation.

Recent experimental results for covalent glasses suggest the existence of an intermediate phase attributed to the self-organization of the glass network resulting from the tendency to minimize its internal stress. However, the exact nature of this experimentally measured phase remains unclear. We modified a previously proposed model of self-organization by generating a uniform sampling of stress-free networks. In our model, studied on a diluted triangular lattice, an unusual intermediate phase appears, in which both rigid and floppy networks have a chance to occur, a result also observed in a related model on a Bethe lattice by Barré et al[Phys. Rev. Lett. 94, 208701 (2005)]. Our results for the bond-configurational entropy of self-organized networks, which turns out to be only about 2% lower than that of random networks, suggest that a self-organized intermediate phase could be common in systems near the rigidity percolation threshold.

Journal Article↗

PubMed2005

Activated sampling in complex materials at finite temperature: the properly obeying probability activation-relaxation technique.

While the dynamics of many complex systems is dominated by activated events, there are very few simulation methods that take advantage of this fact. Most of these procedures are restricted to relatively simple systems or, as with the activation-relaxation technique (ART), sample the conformation space efficiently at the cost of a correct thermodynamical description. We present here an extension of ART, the properly obeying probability ART (POP-ART), that obeys detailed balance and samples correctly the thermodynamic ensemble. Testing POP-ART on two model systems, a vacancy and an interstitial in crystalline silicon, we show that this method recovers the proper thermodynamical weights associated with the various accessible states and is significantly faster than molecular dynamics in the simulations of a vacancy below 700 K.

Journal Article↗

PubMed2005

Navigation and analysis of the energy landscape of small proteins using the activation-relaxation technique.

The resolution of the protein folding problem has been tied to the development of a detailed understanding of the configurational energy or of the free energy landscape associated with these molecules. Using the activation-relaxation technique and a simplified energy model, we present here a detailed analysis of the energy landscape of 16-residue peptide that folds into a beta-hairpin. Our results support the concept of an energy landscape with an effective topology consistent with a scale-free network.

Biophysics↗

PubMed2005

Following the aggregation of amyloid-forming peptides by computer simulations.

There is experimental evidence suggesting that the toxicity of neurodegenerative diseases such as Alzheimer's disease may result from the soluble intermediate oligomers. It is therefore important to characterize extensively the early steps of oligomer formation at atomic level. As these structures are metastable and short lived, experimental data are difficult to obtain and they must be complemented with numerical simulations. In this work, we use the activation-relaxation technique coupled with a coarse-grained energy model to study in detail the mechanisms of aggregation of four lys-phe-phe-glu (KFFE) peptides. This is the shortest peptide known to form amyloid fibrils in vitro. Our simulations indicate that four KFFE peptides adopt a variety of oligomeric states (tetramers, trimers, and dimers) with various orientations of the chains in rapid equilibrium. This conformational distribution is consistent with all-atom molecular-dynamics simulations in explicit solvent and is sequence dependent; as seen experimentally, the lys-pro-gly-glu (KPGE) peptides adopt disordered structures in solution. Our unbiased simulations also indicate that the assembly process is much more complex than previously thought and point to intermediate structures which likely are kinetic traps for longer chains.

Amyloid beta-Peptides↗

PubMed2005

Exploring the early steps of amyloid peptide aggregation by computers.

The assembly of normally soluble proteins into amyloid fibrils is a hallmark of neurodegenerative diseases. Because protein aggregation is very complex, involving a variety of oligomeric metastable intermediates, the detailed aggregation paths and structural characterization of the intermediates remain to be determined. Yet, there is strong evidence that these oligomers, which form early in the process of fibrillogenesis, are cytotoxic. In this paper, we review our current understanding of the underlying factors that promote the aggregation of peptides into amyloid fibrils. We focus here on the structural and dynamic aspects of the aggregation as observed in state-of-the-art computer simulations of amyloid-forming peptides with an emphasis on the activation-relaxation technique.

Amyloid↗

PubMed2004

In silico assembly of Alzheimer's Abeta16-22 peptide into beta-sheets.

Recent studies suggest that soluble oligomers of amyloid-forming peptides have toxic effects in cell cultures. In this study, the folding of three Alzheimer's A beta(16-22) peptides have been simulated with the activation-relaxation technique and a generic energy model. Starting from randomly chosen states, the predicted lowest energy structure superposes within 1 A rms deviation from its conformation within the fibrils. This antiparallel structure is found to be in equilibrium with several out-of-register antiparallel beta-sheets and mixed parallel-antiparallel beta-sheets, indicating that full structural order in the fibrils requires larger aggregates. Folding involves the formation of dimers followed by the addition of a monomer and proceeds through a generalized mechanism between disordered and native alignments of beta-strands.

Amyloid beta-Peptides↗

PubMed2004

Sampling the self-assembly pathways of KFFE hexamers.

The formation of amyloid fibrils is often encountered in Alzheimer's disease, type II diabetes, and transmissible spongiform encephalopathies. In the last few years, however, mounting evidence has suggested that the soluble oligomers of amyloid-forming peptides are also cytotoxic agents. Understanding the early pathway steps of amyloid self-assembly at atomic detail might therefore be crucial for the development of specific inhibitors to prevent amyloidosis in humans. Using the activation-relaxation technique and a generic energy model, we study in detail the aggregation of a hexamer of KFFE peptide. Our simulations show that a monomer remains disordered, but that six monomers placed randomly in an open box self-associate to adopt, with various orientations, three possible distant low-energy structures. Two of these structures show a double-layer beta-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction, whereas the third one consists of a barrel-like curved single-layer hexamer. Based on these results, we propose a bidirectional growth mode of amyloid fibril, involving alternate lateral and longitudinal growths.

Amyloid↗

PubMed2004

Complex folding pathways in a simple beta-hairpin.

The determination of the folding mechanisms of proteins is critical to understand the topological change that can propagate Alzheimer and Creutzfeld-Jakobs diseases, among others. The computational community has paid considerable attention to this problem; however, the associated time scale, typically on the order of milliseconds or more, represents a formidable challenge. Ab initio protein folding from long molecular dynamics simulations or ensemble dynamics is not feasible with ordinary computing facilities and new techniques must be introduced. Here we present a detailed study of the folding of a 16-residue beta-hairpin, described by a generic energy model and using the activation-relaxation technique. From a total of 90 trajectories at 300 K, three folding pathways emerge. All involve a simultaneous optimization of the complete hydrophobic and hydrogen bonding interactions. The first two pathways follow closely those observed by previous theoretical studies (folding starting at the turn or by interactions between the termini). The third pathway, never observed by previous all-atom folding, unfolding, and equilibrium simulations, can be described as a reptation move of one strand of the beta-sheet with respect to the other. This reptation move indicates that non-native interactions can play a dominant role in the folding of secondary structures. Furthermore, such a mechanism mediated by non-native hydrogen bonds is not available for study by unfolding and Gō model simulations. The exact folding path followed by a given beta-hairpin is likely to be influenced by its sequence and the solvent conditions. Taken together, these results point to a more complex folding picture than expected for a simple beta-hairpin.

Amino Acid Sequence↗

PubMed2004

Pathway complexity of Alzheimer's beta-amyloid Abeta16-22 peptide assembly.

Recent studies suggest that both soluble oligomers and insoluble fibrils have toxic effects in cell cultures, raising the interest in determining the first steps of the assembly process. We have determined the aggregation mechanisms of Abeta(16-22) dimer using the activation-relaxation technique and an approximate free energy model. Consistent with the NMR solid-state analysis, the dimer is predicted to prefer an antiparallel beta sheet structure with the expected registry of intermolecular hydrogen bonds. The simulations, however, locate three other antiparallel minima with nonnative beta sheet registries and one parallel beta sheet structure, slightly destabilized with respect to the ground state. This result is significant because it can explain the observed dependency of beta sheet registry on pH conditions. We also find that assembly of Abeta(16-22) into dimers follows multiple routes, but alpha-helical intermediates are not obligatory. This indicates that destabilization of alpha-helical intermediates is unlikely to abolish oligomerization of Abeta peptides.

Amyloid beta-Peptides↗

PubMed2003

Relationship between dynamical heterogeneities and stretched exponential relaxation.

We identify dynamical heterogeneities as an essential prerequisite for stretched exponential relaxation in dynamically frustrated systems. This heterogeneity takes the form of ordered domains of finite but diverging lifetime for particles in atomic or molecular systems, or spin states in magnetic materials. At the onset of the dynamical heterogeneity, the distribution of time intervals spent in such domains or traps becomes stretched exponential at long times. We rigorously show that once this is the case the autocorrelation function of the renewal process formed by these time intervals is also a stretched exponential at long times.

Journal Article↗

PubMed2002

Characterization of the stretched-exponential trap-time distributions in one-dimensional coupled map lattices.

Stretched-exponential distributions and relaxation responses are encountered in a wide range of physical systems such as glasses, polymers, and spin glasses. As found recently, this type of behavior occurs also for the distribution function of a certain trap time in a number of coupled dynamical systems. We analyze a one-dimensional mathematical model of coupled chaotic oscillators that reproduces an experimental setup of coupled diode resonators and identify the necessary ingredients for stretched-exponential distributions.

Journal Article↗