All-atom molecular dynamics studies of the full-length β-amyloid peptides

beta-Amyloid peptides are believed to play an essential role in Alzheimer's disease (AD), due to their sedimentation in the form of beta-amyloid aggregates in the brain of AD-patients, and the in vitro neurotoxicity of oligomeric aggregates. The monomeric peptides come in different lengths of 39-43 residues, of which the 42 alloform seems to be most strongly associated with AD-symptoms. Structural information on these peptides to date comes from NMR studies in acidic solutions, organic solvents, or on shorter fragments of the peptide. In addition X-ray and solid-state NMR investigations of amyloid fibrils yield insight into the structure of the final aggregate and therefore define the endpoint of any conformational change of an A beta-monomer along the aggregation process. The conformational changes necessary to connect the experimentally known conformations are not yet understood and this process is an active field of research. In this paper, we report results from all-atom molecular dynamics simulations based on experimental data from four different peptides of 40 amino acids and two peptides consisting of 42 amino acids. The simulations allow for the analysis of intramolecular interactions and the role of structural features. In particular, they show the appearance of P-turn in the region between amino acid 21 and 33, forming a hook-like shape as it is known to exist in the fibrillar A beta-structures. This folding does not depend on the formation of a salt bridge between Asp-23 and Lys-28 but requires the A beta(1-42) as such structure was not observed in the shorter system A beta(1-40). (c) 2005 Elsevier B.V. All rights reserved.