A� micelle-like oligomers have often been observed by AFM and EM, but with a wide range of size distributions from 3 nm to 35 nm. Different sizes of spherical aggregates appear to be the precursor for the other oligomers or nucleated seeds at the very early stage of aggregation process, representing different assembly stages or paths to mature fibrils. Despite of their pathological importance, atomic structures of A�-micelles are still not available, primarily because of their small size, short-life time, and low concentration.In this work, we develop a computational strategy including conformational search, structural optimization, potential energy evaluation, and all-atom molecular dynamics (MD) to predict and model atomic structures of A�25-35 micelles at the very early stage of aggregation process. Four hypothetical micelle-like structures with ~50 � in diameter consisting of 62 A�25-35 peptides are selected from 2016 candidates by optimizing interpeptide organizations and surface hydrophobicity and by further refining interpetide displacements and intrapeptide self-rotation. Those four selected micelle-like structures with the lowest packing energies are subsequently subject to explicit-solvent MD simulations for comparison. Simulations show that the micelles with antiparallel interpeptide organization display higher structural stability than those with parallel organization, resulting from the optimization of geometrical sidechain match among peptides, surface hydrophobicity, and electrostatic interactions. Comparative energy analysis shows that peptide-water interactions are dominant forces for stabilizing the micelles in solution, while internal interactions provide additional favorable energy for secondary structure conversion among turn, coil, helix, and less extent of �-strand.

Structural characterization of Aβ micelles using molecular modeling and dynamics simulations

239th National Meeting (2010)

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