title: Dimerization Mechanism of Alzheimer Aβ40Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation.
abstract: Amyloid beta (Aβ) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Aβ40dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Aβ40dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of-register antiparallel β-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded β-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid-forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded β-sheet or inhibiting the formation of an interpeptide β-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of Aβ species.
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, IBPC, Université Paris Diderot, Sorbonne Paris Cité , 13 Rue Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Phuong H
authors.initials: PH
authors.lastname: Nguyen
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, IBPC, Université Paris Diderot, Sorbonne Paris Cité , 13 Rue Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sterpone
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Catalonia, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Pouplana
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, IBPC, Université Paris Diderot, Sorbonne Paris Cité , 13 Rue Pierre et Marie Curie, 75005 Paris, France.|IUF (Institut Universitaire de France) , 103 Boulevard Michel, 75005 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona , 08028 Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campanera
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D000072757:Protein Conformation, beta-Strand; D055503:Protein Multimerization; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; C078592:amyloid beta-protein (1-40)