Amyloid-? (A?42) Peptide Aggregation Rate and Mechanism on Surfaces with Widely Varied Properties: Insights from Brownian Dynamics Simulations.

ABSTRACT: Amyloid-? (A?) plaques, which form by aggregation of harmless A? peptide monomers into larger fibrils, are characteristic of neurodegenerative disorders such as Alzheimer's disease. Efforts to treat Alzheimer's disease focus on stopping or reversing the aggregation process that leads to fibril formation. However, effective treatments are elusive due to certain unknown aspects of the process. Many hypotheses point to disruption of cell membranes by adsorbed A? monomers or oligomers, but how A? behaves and aggregates on surfaces of widely varying properties, such as those present in a cell, is unclear. Elucidating the effects of various surfaces on the dynamics of A? and the kinetics of the aggregation process from bulk solution to a surface-adsorbed multimer can help identify what drives aggregation, leading to new methods of intervention by inhibitory drugs or other means. In this work, we used all-atom Brownian dynamics simulations to study the association of two distinct A?42 monomer conformations with a surface-adsorbed or free-floating A?42 dimer. We calculated the association time, surface interaction energy, surface diffusion coefficient, surface residence time, and the mechanism of association on four different surfaces and two different bulk solution scenarios. In the presence of a surface, the majority of monomers underwent a two-dimensional surface-mediated association that depended primarily on an A?42 electrostatic interaction with the self-assembled monolayer (SAM) surfaces. Moreover, aggregation could be inhibited greatly by surfaces with high affinity for A?42 and heterogeneous charge distribution. Our results can be used to identify new opportunities for disrupting or reversing the A?42 aggregation process.

SUBMITTER: Cholko T 

PROVIDER: S-EPMC7797022 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature