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 (Aβ16-22), promoted long-lived and highly beta-sheet-like domains in the peptide oligomers. Concomitantly, heparin-Aβ16-22 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 Aβ16-22 oligomers, thus offering insights into the contrasting inhibition of fibrillation by the relatively rigid polysaccharide, chitosan.
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