Molecular Insights into the Dynamics of Amyloid Fibril Growth: Elongation and Lateral Assembly of GNNQQNY Protofibrils

Abstract

The self-assembly of peptides and proteins into β-sheet rich amyloid fibrils is linked to both functional and pathological states. In this study, the growth of fibrillar structures of the short peptide GNNQQNY, a fragment from the yeast prion Sup35 protein, was examined. Molecular dynamics simulations were used to study alternative mechanisms of fibril growth, including elongation through binding of monomers as well as fibril self-assembly into larger, more mature structures. It was found that after binding, monomers diffused along preformed fibrils toward the ends, supporting the mechanism of fibril growth via elongation. Lateral assembly of protofibrils was found to occur readily, suggesting that this could be the key to transitioning from isolated fibrils to mature multilayer structures. Overall, the work provides mechanistic insights into the competitive pathways that govern amyloid fibril growth.

Peptide Self-Assembly into Amyloid Fibrils: Unbiased All-Atom Simulations

“…In particular, the Aβ(16–22) peptide was shown to form fibrils within a time frame of 2 μs using variants of the CHARMM36m force field, whereas fibrils did not form successfully using AMBER99SB-disp. , In another study, the amphipathic (FKFE) 2 peptide was shown to form a fibril using the AMBER99SB-ildn force field, and at high peptide concentrations, increasing temperature was shown to accelerate this process . In the same vein, simulations with a preformed fibril and a few peptides randomly located in the simulation box were used to study fibril growth − and secondary nucleation . These studies are opening the door to our understanding of the sequence of molecular events leading to fibril formation.…”