In silico studies of the early stages of aggregation of A β42 peptides

Abstract

Abstract: Accumulation of amyloid beta (Aβ) peptide in the brain is responsible for debilitating neurodegenerative disease, namely, Alzheimer’s disease. We have carried out atomistic molecular dynamics simulation to study the early stages of the aggregation process of five full-length Aβ42 peptide monomers with varying secondary structural contents in aqueous solution. Attempts have been made to study the conformational modifications of the Aβ peptide monomers and their dynamical features during the oligomer formation. In particular, specific molecular interactions that drive the association process leading to the formation of the stable oligomer have been identified. The calculations revealed that the helix–helix linkage plays an important role for bringing the unstructured regions of the monomers closer for self-assembly. Importantly, it is demonstrated that the contribution originating from the nonpolar interactions between the peptides and the corresponding nonpolar solvation more than compensates the weakening effect of unfavorable inter-peptide electrostatic interactions, thereby stabilizing the nucleated oligomer. Graphical Abstract: Molecular dynamics simulations were performed to probe the early stages of aggregation of Aβ42 peptides. The calculations revealed that the helix–helix linkage plays an important role for bringing the unstructured regions of the monomers closer for self-assembly. Further, the nucleated oligomer was found to be stabilized primarily by nonpolar inter-peptide interactions. [Figure not available: see fulltext.].