Replica Exchange Simulations of the Thermodynamics of Aβ Fibril Growth

Replica exchange molecular dynamics and an all-atom implicit solvent model are used to probe the thermodynamics of deposition of Alzheimer's A beta monomers on preformed amyloid fibrils. Consistent with the experiments, two deposition stages have been identified. The docking stage occurs over a wide temperature range, starting with the formation of the first peptide-fibril interactions at 500 K. Docking is completed when a peptide fully adsorbs on the fibril edge at the temperature of 380 K. The docking transition appears to be continuous, and occurs without free energy barriers or intermediates. During docking, incoming A beta monomer adopts a disordered structure on the fibril edge. The locking stage occurs at the temperature of approximate to 360 K and is characterized by the rugged free energy landscape. Locking takes place when incoming A beta peptide forms a parallel beta-sheet structure on the fibril edge. Because the beta-sheets formed by locked A beta peptides are typically off-registry, the structure of the locked phase differs from the structure of the fibril interior. The study also reports that binding affinities of two distinct fibril edges with respect to incoming A beta peptides are different. The peptides bound to the concave edge have significantly lower free energy compared to those bound on the convex edge. Comparison with the available experimental data is discussed.