Exploring the structural conformations of amyloid-beta oligomers on self-assembled monolayers and in water under confinement, a molecular dynamics study.

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder, affecting millions of people worldwide. The aggregation of amyloid-beta (Aβ) peptides and the intermediate protein tau into amyloid fibrils is believed to be a critical event in the pathogenesis of AD. Amyloid fibrils represent the endpoints of aggregation, and it is widely believed that their precursors—the soluble oligomers—are the more important neurotoxins. However, there is limited structural information available on Aβ oligomers. Although atomic force microscopy (AFM) is a widely-used method employed to study the conformation of Aβ oligomers, the resolution of AFM is limited and unable to discern atomistic structural features. Here, we construct a self-assembled monolayer (SAM), mimicking the surface properties of mica (used in AFM), with varying surface charge densities. Then, we apply the enhanced sampling algorithm REST2 (replica exchange with solute tempering) from the NAMD package, to efficiently sample the protein conformations on the SAM surface. Our simulations have resulted in cross β-sheet formation between Aβ monomers, similar to that observed experimentally. In particular, we find that residues 17-21 and 35-40 are involved in β-sheet formation, the former of which has been observed in the Aβ fibril structure. We also observe the prominence of the intramolecular Asp23-Lys28 salt bridge, which has been found to play a significant role in the formation of Aβ fibrils. Further, we notice that an asymmetric charge distribution on the SAM surface tends to result in greater β-sheet formation. Our simulations of Aβ monomers in TIP4P water, confined using a harmonic wall, similarly result in cross β-sheet formation among the monomers. Confinement has been found to increase the conformational stability of proteins, suggesting the possibility of Aβ formation in the crowded environment of the cell.