Structural determination of Abeta25-35 micelles by molecular dynamics simulations

Amyloid-beta (Abeta) peptides and other amyloidogenic proteins can form a wide range of soluble oligomers of varied morphologies at the early aggregation stage, and some of these oligomers are biologically relevant to the pathogenesis of Alzheimer's disease. Spherical micelle-like oligomers have been often observed for many different types of amyloids. Here, we report a hybrid computational approach to systematically construct, search, optimize, and rank soluble micelle-like Abeta25-35 structures with different side-chain packings at the atomic level. Simulations reveal for the first time, to our knowledge, that two Abeta micelles with antiparallel peptide organization and distinct surface hydrophobicity display high structural stability. Stable micelles experience a slow secondary structural transition from turn to alpha-helix. Energetic analysis coupled with computational mutagenesis reveals that van der Waals and solvation energies play a more pronounced role in stabilizing the micelles, whereas the electrostatic energies present a stable but minor energetic contribution to peptide assemblies. Modeled Abeta micelles with shapes and dimensions similar to those of experimentally derived spherical structures also provide detailed information about the roles of structural dynamics and transition in the formation of amyloid fibrils. The strong binding affinity of our micelles to antibodies implies that micelles may be a biologically relevant species.