title: Structures of the Alzheimer's Wild-Type Aβ1-40 Dimer from Atomistic Simulations.
abstract: We have studied the dimer of amyloid beta peptide Aβ of 40 residues by means of all-atom replica exchange molecular dynamics. The Aβ-dimers have been found to be the smallest toxic species in Alzheimer's disease, but their inherent flexibilities have precluded structural characterization by experimental methods. Though the 24-μs-scale simulation reveals a mean secondary structure of 18% β-strand and 10% α helix, we find transient configurations with an unstructured N-terminus and multiple β-hairpins spanning residues 17-21 and 30-36, but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all α topologies, and one compact peptide with β-sheet structure stabilized by a rather extended peptide with α-helical content. Overall, this first all-atom study provides insights into the equilibrium structure of the Aβ1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early-stage Alzheimer's disease on a molecular level.
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: Bogdan
authors.initials: B
authors.lastname: Tarus
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: Thanh T
authors.initials: TT
authors.lastname: Tran
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: Jessica
authors.initials: J
authors.lastname: Nasica-Labouze
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: 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: Philippe
authors.initials: P
authors.lastname: Derreumaux
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014867:Water