Molecular dynamics simulations of Alzheimer's beta-amyloid protofilaments.

0022-2836/$ see front matter Published Abbreviations used: MD, molecu mass-per-length; STEM, scanning tr microscopy; RMSD, root-mean-squa particle mesh Ewald. E-mail address of the correspond gerhard.hummer@nih.gov Filamentous amyloid aggregates are central to the pathology of Alzheimer’s disease. We use all-atom molecular dynamics (MD) simulations with explicit solvent and multiple force fields to probe the structural stability and the conformational dynamics of several models of Alzheimer’s b-amyloid fibril structures, for both wild-type and mutated amino acid sequences. The structural models are based on recent solid state NMR data. In these models, the peptides form in-register parallel b-sheets along the fibril axis, with dimers of two U-shaped peptides located in layers normal to the fibril axis. Four different topologies are explored for stacking the b-strand regions against each other to form a hydrophobic core. Our MD results suggest that all four NMR-based models are structurally stable, and we find good agreement with dihedral angles estimated from solid-state NMR experiments. Asp23 and Lys28 form buried salt-bridges, resulting in an alternating arrangement of the negatively and positively charged residues along the fibril axis that is reminiscent of a one-dimensional ionic crystal. Interior water molecules are solvating the buried salt-bridges. Based on data from NMR measurements and MD simulations of short amyloid fibrils, we constructed structural models of long fibrils. Calculated X-ray fiber diffraction patterns show the characteristics of packed b-sheets seen in experiments, and suggest new experiments that could discriminate between various fibril topologies. Published by Elsevier Ltd.