Contrasting Effects of Soft and Hard Crowders on Amyloid Aggregation

Abstract

Pathological amyloid proteins are involved in degenerative and neuro-degenerative diseases such as Alzheimer's, Parkinson's diseases, type II diabetes and so forth. Amyloid cytotoxicity has been postulated to primarily stem from oligomers rather than mature fibrils because of the ease permeation to membranes. Amyloid aggregation in vivo takes place in highly crowed environment, therefore, it is important to investigate the crowding effects on the oligomerization and fibrillization of amyloid proteins and peptides. Many efforts have been devoted to uncover the steric effects of crowders on protein folding and peptide aggregation. However, there is a lack of study regarding the effects of direct inter-molecular interactions known as soft interaction between protein crowders and proteins on amyloid aggregation. In this study, we employed all-atom discrete molecular dynamics simulations to delineate the effects of soft and steric interactions between crowders and amyloid peptides on amyloid aggregation. Specifically, we used the amyloidogenic fragment 25-35 of Amyloid-β (Aβ25-35) as the model amyloid peptides and two abundant proteins components in cellular environments - actin and collagen fragments - as protein crowders. The steric effects were modeling by assigning hard-core interactions between protein crowders and amyloid peptides. Our simulation results uncovered contrasting effects of steric and soft interactions crowders on Aβ25-35 aggregation, where steric crowders promoted Aβ25-35 amyloid aggregation but the interacting crowders inhibited Aβ25-35 amyloid. Increasing volume ratio of crowders enhance the corresponding effects of two different crowders. Our computational study provides for the first time the detail aggregation mechanism of amyloids under cellular environments by consideration of non-specific interactions and excluded volume effects.