Side chain interactions can impede amyloid fibril growth: replica exchange simulations of Abeta peptide mutant.

Using replica exchange molecular dynamics, we study the effect of Asp23Tyr mutation on Abeta(10-40) fibril growth. The effect of this mutation is revealed through the computation of free energy landscapes, the distributions of peptide-fibril interactions, and by comparison with the wild-type Abeta(10-40) peptide. Asp23Tyr mutation has a relatively minor influence on the docking of Abeta peptides to the fibril. However, it has a strong impact on the locking stage due to profound stabilization of the parallel in-registry beta-sheets formed by the peptides on the fibril edge. The enhanced stability of parallel beta-sheets results from the deletion of side chain interactions formed by Asp23, which are incompatible with the fibril-like conformers. Consequently, Asp23Tyr mutation is expected to promote fibril growth. We argue that strong off-registry side chain interactions may slow down fibril assembly as it occurs for the wild-type Abeta peptide. The analysis of experimental data offers support to our in silico conclusions.