Sequence Dependence of Amyloid Fibril Formation: Insights from Molecular Dynamics Simulations

The clarification of the physico-chemical determinants underlying amyloid deposition is critical for our understanding of misfolding diseases. With this purpose we have performed a systematic all-atom molecular dynamics (MD) study of a series of single point mutants of the de novo designed amyloidogenic peptide STVIIE. Sixteen different 50 ns long simulations using explicit solvent have been carried out starting from four different conformations of a polymeric six-stranded β-sheet. The simulations have provided evidence for the influence of a small number of site-specific hydrophobic interactions on the packing and stabilization of nascent aggregates, as well as the interplay between side-chain interactions and the net charge of the molecule on the strand arrangement of polymeric β-sheets. This MD analysis has also shed light into the origin of the position dependence on mutation of β-sheet polymerization that was found experimentally for this model system. Our results suggest that MD can be applied to detect critical positions for β-sheet aggregation within a given amyloidogenic stretch. Studies similar to the one presented here can guide site-directed mutations or the design of drugs that specifically disrupt the key stabilizing interactions of β-sheet aggregates.