Étudiant au doctorat en biophysique.
Projets de recherche
- Protéine bêta-amyloïde
- Protéine de huntingtine
- Interactions membranes protéines
- Développement de potentiel à gros-grains
Articles en collaboration
V. Binette, S. Côté, N. Mousseau, Free energy Landscape of the Amino-terminal Fragment of Huntingtin in Aqueous Solution, Biophysical Journal (2016).
S. Côté, V. Binette, E. S. Salnikov, B. Bechinger, N. Mousseau, Probing the Huntingtin 1-17 Membrane Anchor on a Phospholipid Bilayer by Using All-Atom Simulations, Biophysical Journal 108, 1187-1198 (2015).Résumé : Mislocalization and aggregation of the huntingtin protein are related to Huntington?s disease. Its first exon?more specifically the first 17 amino acids (Htt17)?is crucial for the physiological and pathological functions of huntingtin. It regulates huntingtin?s activity through posttranslational modifications and serves as an anchor to membrane-containing organelles of the cell. Recently, structure and orientation of the Htt17 membrane anchor were determined using a combined solution and solid-state NMR approach. This prompted us to refine this model by investigating the dynamics and thermodynamics of this membrane anchor on a POPC bilayer using all-atom, explicit solvent molecular dynamics and Hamiltonian replica exchange. Our simulations are combined with various experimental measurements to generate a high-resolution atomistic model for the huntingtin Htt17 membrane anchor on a POPC bilayer. More precisely, we observe that the single α-helix structure is more stable in the phospholipid membrane than the NMR model obtained in the presence of dodecylphosphocholine detergent micelles. The resulting Htt17 monomer has its hydrophobic plane oriented parallel to the bilayer surface. Our results further unveil the key residues interacting with the membrane in terms of hydrogen bonds, salt-bridges, and nonpolar contributions. We also observe that Htt17 equilibrates at a well-defined insertion depth and that it perturbs the physical properties?order parameter, thickness, and area per lipid?of the bilayer in a manner that could favor its dimerization. Overall, our observations reinforce and refine the NMR measurements on the Htt17 membrane anchor segment of huntingtin that is of fundamental importance to its biological functions.
C. Guo, S. Côté, N. Mousseau, G. Wei, Distinct Helix Propensities and Membrane Interactions of Human and Rat IAPP1–19 Monomers in Anionic Lipid Bilayers, The Journal of Physical Chemistry B 119, 3366-3376 (2015).Résumé : Islet amyloid polypeptide, IAPP or amylin, is a 37-residue peptide hormone coexpressed with insulin by pancreatic ?-cells. The aggregation of human IAPP (hIAPP) into amyloid deposits is associated with type II diabetes. Substantial evidence suggests that the interaction of anionic membranes with hIAPP may facilitate peptide aggregation and the N-terminal 1?19 fragment (IAPP1?19) plays an important role in peptide?membrane interaction. As a first step to understand how structural differences between human and rat IAPP peptides in membranes may influence the later oligomerization process, we have investigated the structures and orientations of hIAPP1?19 and the less toxic rIAPP1?19 (i.e., the H18R mutant of hIAPP1?19) monomers in anionic POPG bilayers by performing replica exchange molecular dynamics (REMD) simulations. On the basis of ?20 ?s REMD simulations started from a random coil conformation of the peptide placed in water, we find that unfolded h(r)IAPP1?19 can insert into the bilayers and the membrane-bound peptide stays mainly at the lipid head?tail interface. hIAPP1?19 displays higher helix propensity than rIAPP1?19, especially in the L12?L16 region. The helix is oriented parallel to the bilayer surface and buried in the membrane 0.3?0.8 nm below the phosphorus atoms, consistent with previous electron paramagnetic resonance data. The helical conformation is an amphiphilic helix with its hydrophilic and hydrophobic faces pointing, respectively, to the lipid head and tail regions. The H18R substitution enhances the electrostatic interactions of IAPP1?19 with the membrane, while it weakens the intrapeptide interactions crucial for helix formation, thus leading to lower helix propensity of rIAPP1?19. Implications of our simulation results on the membrane-mediated IAPP1?19 oligomerization are discussed.
J. Nasica-Labouze, P. H. Nguyen, F. Sterpone, O. Berthoumieu, N. - V. Buchete, S. Coté, et al., Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies, Chemical Reviews 115, 3518-3563 (2015).
S. Côté, G. Wei, N. Mousseau, Atomistic mechanisms of huntingtin N-terminal fragment insertion on a phospholipid bilayer revealed by molecular dynamics simulations, Proteins: Structure, Function, and Bioinformatics 82, 1409-1427 (2014).Résumé : The huntingtin protein is characterized by a segment of consecutive glutamines (QN) 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 (httNT) positioned just before the QN 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 httNTQN 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 httNT peptide forms a stable α-helix essentially parallel to the membrane with its nonpolar 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 httNT peptide. These observations do not significantly change upon adding the QN region whose role is rather to provide, through its hydrogen bonds with the phospholipids' head group, a stable scaffold facilitating the partitioning of the httNT region in the membrane. Moreover, by staying accessible to the solvent, the amyloidogenic QN region could also play a key role for the oligomerization of httNTQN on phospholipid membranes. Proteins 2014; 82:1409–1427. © 2014 Wiley Periodicals, Inc.
S. Côté, G. Wei, N. Mousseau, All-Atom Stability and Oligomerization Simulations of Polyglutamine Nanotubes with and without the 17-Amino-Acid N-Terminal Fragment of the Huntingtin Protein, The Journal of Physical Chemistry B 116, 12168-12179 (2012).Résumé : 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 ?-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 (httNT). 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 ?-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 httNT enhances the structural stability of the ?-rich seeds, suggesting a new mechanism by which it can increase the aggregation rate of the amyloidogenic polyQ sequence.
S. Côté, R. Laghaei, P. Derreumaux, N. Mousseau, Distinct Dimerization for Various Alloforms of the Amyloid-Beta Protein: Aβ1–40, Aβ1–42, and Aβ1–40(D23N), The Journal of Physical Chemistry B 116, 4043-4055 (2012).Résumé : 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: A?1?40 and A?1?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 A? dimer, however, and to complement experimental observations, we simulated the folding of the wild-type A?1?40 and A?1?42 dimers as well as the mutated A?1?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 and K28 seen in the wild-type A?, leading to very different fibrillation properties and final amyloid fibrils. Our results show that the A?1?42 dimer has a higher propensity than the A?1?40 dimer to form ?-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 A?. The free energy landscape of the A?1?42 dimer is also broader and more complex than that of the A?1?40 dimer. Interestingly, D23N also impacts the free energy landscape by increasing the population of configurations with higher ?-strand propensities when compared against A?40. In addition, while A?1?40(D23N) displays a higher ?-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 A? dimer.
S. Côté, P. Derreumaux, N. Mousseau, Distinct Morphologies for Amyloid Beta Protein Monomer: Aβ1–40, Aβ1–42, and Aβ1–40(D23N), Journal of Chemical Theory and Computation 7, 2584-2592 (2011).Résumé : Numerous experimental studies indicate that amyloid beta protein (A?) oligomers as small as dimers trigger Alzheimer?s disease. Precise solution conformation of A? monomer is missing since it is highly dynamic and aggregation prone. Such a knowledge is however crucial to design drugs inhibiting oligomers and fibril formation. Here, we determine the equilibrium structures of the A?1?40, A?1?42, and A?1?40(D23N) monomers using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics simulations. We observe that even if these three alloforms are mostly disordered at the monomeric level, in agreement with experiments and previous simulations on A?1?40 and A?1?42, striking morphological differences exist. For instance, A?1?42 and A?1?40(D23N) have higher ?-strand propensities at the C-terminal, residues 30?42, than A?1?40. The D23N mutation enhances the conformational freedom of the residues 22?29 and the propensity for turns and ?-strands in the other regions. It also changes the network of contacts; the N-terminal (residues 1?16) becoming more independent from the rest of the protein, leading to a less compact morphology than the wild-type sequence. These structural properties could explain in part why the kinetics and the final amyloid products vary so extensively between the A?1?40 and the A?1?40(D23N) peptides.