Modeling the alpha-helix to beta-hairpin transition mechanism and the formation of oligomeric aggregates of the fibrillogenic peptide Abeta(12-28): insights from all-atom molecular dynamics simulations.

In this paper, all-atom molecular dynamics simulations in explicit solvent are used to investigate the structural and dynamical determinants of the alpha-helical to beta-hairpin conformational transition of the 12-28 fragment from the full length Abeta Alzheimer's peptide. The transition from alpha-helical to beta-structure requires the peptide to populate intermediate beta-bend geometries in which several mainly hydrophobic interactions are partially formed. This is followed by the sudden collapse to ordered beta-hairpin structures and the simultaneous disruption of the hydrophobic side-chain interactions with a consequent increase in solvent exposure. The solvent exposure of hydrophobic side-chains belonging to a sequence of five consecutive residues in the beta-hairpin defines a possible starting point for the onset of the aggregation mechanisms. Several different conformations of model oligomeric (dimeric and tetrameric) aggregates are then investigated. These simulations show that while hydrophobic contacts are important to bring together different monomers with a beta-hairpin like conformation, more specific interactions such as hydrogen-bonding and coulombic interactions, should be considered necessary to provide further stabilization and ordering to the nascent fibrillar aggregates.