Unravelling heparin's enhancement of amyloid aggregation in a model peptide system

Abstract

A coarse-grained (CG) model for heparin, an anionic polysaccharide, was developed to investigate the mechanisms of heparin's enhancement of fibrillation in many amyloidogenic peptides. CG molecular dynamics simulations revealed that heparin, by forming contacts with the model amyloidogenic peptide, amyloid-β's K₁₆LVFFAE₂₂ fragment (Aβ_16–22), promoted long-lived and highly beta-sheet-like domains in the peptide oligomers. Concomitantly, heparin-Aβ_16–22 contacts suppressed the entropy of mixing of the oligomers’ beta-domains. Such oligomers could make better seeds for fibrillation, potentially contributing to heparin's fibril-enhancing behaviour. Additionally, reductions in heparin's flexibility led to delayed aggregation, and less ordered Aβ_16–22 oligomers, thus offering insights into the contrasting inhibition of fibrillation by the relatively rigid polysaccharide, chitosan.