Computational studies of the structure, dynamics and native content of amyloid-like fibrils of ribonuclease A

The characterization at atomic resolution of amyloid-like protein
aggregates is one of the fundamental problems of modern biology. In
particular, the question whether native-like domains are retained or
completely refolded in the amyloid state and the identification of
possible mechanisms for macromolecular ordered aggregation represent
major unresolved puzzles. To address these issues, in this article we
examine the stability, dynamics, and conservation of native-like
properties of several models of a previously designed amyloid-like
fibril of RNase A (Sambashivan et al., Nature 2005, 437:266-269).
Through the use of molecular dynamics (MD) simulations, we have provided
molecular-level insights into the role of different parts of the
sequence on the stability of fibrils, the collective properties of
supramolecular complexes, and the presence of native-like conformations
and dynamics in supramolecular aggregates. We have been able to show
that within the fibrils the three-dimensional globular domain-swapped
units preserve the conformational, dynamical, and hydration properties
typical of the monomeric state, providing a rationalization for the
experimentally observed catalytic activity of fibrils. The nativeness of
the globular domains is not affected by the amyloidogenic stretches,
which determine the molecular recognition process underlying aggregation
through the formation of a stable steric zipper motif. Moreover, through
the study of the hydration features of a single sheet model, we have
been able to show that polyglutamine stretches of the domain-swapped
ribonuclease tend to minimize the interaction with water in favor of
sidechain-sidechain interactions, shedding light on the factors leading
to the supramolecular assembly of beta-sheet layers into dry steric
zippers.