title: Impact of the A2V Mutation on the Heterozygous and Homozygous Aβ1-40 Dimer Structures from Atomistic Simulations.
abstract: The A2V mutation was reported to protect from Alzheimer's disease in its heterozygous form and cause an early Alzheimer's disease type dementia in its homozygous form. Experiments showed that the aggregation rate follows the order A2V > WT (wild-type) > A2V-WT. To understand the impact of this mutation, we carried out replica exchange molecular dynamics simulations of Aβ1-40 WT-A2V and A2V-A2V dimers and compared to the WT dimer. Our atomistic simulations reveal that the mean secondary structure remains constant, but there are substantial differences in the intramolecular and intermolecular conformations upon single and double A2V mutation. Upon single mutation, the intrinsic disorder is reduced, the intermolecular potential energies are reduced, the population of intramolecular three-stranded β-sheets is increased, and the number of all α dimer topologies is decreased. Taken together, these results offer an explanation for the reduced aggregation rate of the Aβ1-40 A2V-WT peptides and the protective effect of A2V in heterozygotes.
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 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, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 Rue Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sterpone
authors.affiliation: Departament de Fisicoquimica, Facultat de Farmacia, Universitat de Barcelona , 08028 Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campanera
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 Rue Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nasica-Labouze
authors.affiliation: Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Paris Diderot, Sorbonne Paris Cité, IBPC, 13 Rue Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology*; D017433:Protein Structure, Secondary / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
keywords: A2V mutation; Amyloid; Aβ peptide; atomistic simulations; dimers