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
beta-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 beta-sheets. This MD analysis has
also shed light into the origin of the position dependence on mutation
of beta-sheet polymerization that was found experimentally for this
model system. Our results suggest that MD can be applied to detect
critical positions for beta-sheet aggregation within a given
amyloiclogenic 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 beta-sheet aggregates. (c)
2005 Published by Elsevier Ltd.