Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics

Fibrils formed by the beta-amyloid (A beta) 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 A beta((9-40)) fibrils. In particular, an unstructured monomer was allowed to interact freely with an A beta 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 theta and backbone virtual-bond- dihedral angle gamma of each residue and principal components, respectively, were analyzed. Also; thermal unbinding (unfolding) of an A beta peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of A beta 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 normative 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.