Structure and sequence determinants of aggregation investigated with molecular dynamics

Spontaneous self-assembly and amyloid formation are a general property
of many polypeptides and the information controlling these processes is
encoded in the sequence. This determines the form and structural
features of the interacting partners that regulate the properties of the
final aggregates. Understanding the correlations between sequence,
structure and dynamics in peptides and proteins at an atomistic level of
resolution still represents one of the grand challenges of modern
biological chemistry. In this context, computer simulations represent a
valuable approach to understand recognition and spontaneous
self-organization, processes that cannot be directly observed
experimentally. Herein, we will discuss cases illustrating the extent to
which simulations can be used to understand the self-organization
properties of natural and designed amyloidogenic peptide sequences. The
simulations provide evidence for the influence of specific interactions
with well defined stereochemical constraints on fibril formation. The
results from our and other groups suggest that simulations can be
applied to detect the critical physico-chemical determinants of a
certain process and can be helpful in the design of new chemical systems
and experiments.