Misfolding of the amyloid beta-protein: A molecular dynamics study

Amyloid beta-proteins spontaneously aggregate and build plaques in the
brains of Alzheimer's disease patients. The polypeptide has been the
subject of extensive in vitro and computational research. Still, the
pathway to aggregational forms and their exact conformations remain
largely unclear. Here we present an extensive molecular dynamics
approach simulating the protein in various temperatures, pH conditions,
and with different charge states of the N- and C-termini, thus exploring
the conformational space of the protein at large. Our results show that
the protein is able to sample different conformations, many of which are
rich in beta structure content, and all characterized by a rapid loss of
helix 1 that converts into a pi-helix, while helix 2 samples random and
beta-rich structures. Moreover, a hydrophobic cluster is observed
involving Val18, Phe19, Ala21, and Gly25. The results are carefully
compared with recent NMR and spectroscopic data, and are in global
agreement with the experimental findings.