Computational studies of protein aggregation mediated by amyloid: Fibril elongation and secondary nucleation

Abstract

Amyloid formation by proteins and peptides is the hallmark of many diseases. Growing evidence suggests that oligomeric species arising during aggregation are toxic, but the molecular mechanism of aggregation and oligomer generation remains unclear. Recent discoveries that amyloid fibrils can convert soluble proteins into oligomeric nuclei to facilitate aggregation highlight the role played by fibrils in protein aggregation. We review here computational studies conducted to elucidate the molecular mechanism of two fibril-dependent processes during protein aggregation, namely, secondary nucleation and fibril elongation. Secondary nucleation occurs on the lateral surface of a fibril to generate nuclei while fibril elongation, through addition of proteins to the ends of fibrils increases the lateral surface of the fibril. We summarize the molecular insights into each process unraveled by computational methods at levels ranging from coarse-grained to atomic and discuss the connection between these insights and experimental observations. The computational challenges faced by these studies and their solutions are also discussed. Finally, we propose possible computational studies that could shed light on the mechanistic aspects of secondary nucleation and fibril elongation that have been unaddressed.

Keywords: Amyloid polymorphism; Coarse-graining; Heterogenous catalysis; Molecular dynamics; Protein-protein interaction; Surface-induced aggregation.