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 β (10-35) (Aβ 10-35) peptide were probed using replica-exchange molecular dynamics (REMD) simulations in explicit solvent. The Aβ 10-35 peptide is a fragment of the full-length Aβ 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 Aβ 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 α-helical or β-sheet structure. The 3D structure of Aβ 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 Aβ fibrils and our simulations suggest that monomeric conformations of Aβ 10-35 contain pre-folded structural motifs that promote rapid aggregation of this peptide.