The structure of the Alzheimer amyloid β 10-35 peptide probed through replica-exchange molecular dynamics simulations in explicit solvent

The conformational states sampled by the Alzheimer amyloid beta (10-35) (A beta 10-35) peptide were probed using replica-exchange molecular dynamics (REMD) simulations in explicit solvent. The A 10-35 peptide is a fragment of the full-length A 40/42 peptide that possesses many of the amyloidogenic properties of its full-length counterpart. Under physiological temperature and pressure, our simulations reveal that the A 10-35 peptide does not possess a single unique folded state. Rather, this peptide exists as a mixture of collapsed globular states that remain in rapid dynamic equilibrium with each other. This conformational ensemble is dominated by random coil and bend structures with insignificant presence of an ahelical or beta-sheet structure. The 3D structure of A beta 10-35 is seen to be defined by a salt bridge formed between the side-chains of K28 and D23. This salt bridge is also observed in A fibrils and our simulations suggest that monomeric conformations of A beta 10-35 contain pre-folded structural motifs that promote rapid aggregation of this peptide. (c) 2006 Elsevier Ltd. All rights reserved.