title: Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics.
abstract: Fibrils formed by the β-amyloid (Aβ) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Aβ(9-40)fibrils. In particular, an unstructured monomer was allowed to interact freely with an Aβ fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an Aβ peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of Aβ fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first "docking" stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally observed "stop-and-go" mechanism of fibril growth.
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
authors.forename: Nika
authors.initials: N
authors.lastname: Maisuradze
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
authors.forename: Khatuna
authors.initials: K
authors.lastname: Kachlishvili
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Scheraga
authors.affiliation: Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
authors.forename: Gia G
authors.initials: GG
authors.lastname: Maisuradze
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D055592:Biophysical Phenomena; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments
keywords: Aβ peptide; UNRES force field; amyloids; replica-exchange molecular dynamics; thermal unfolding; “stop-and-go” mechanism