Fischell Department of Engineering, University of Maryland, College Park, Maryland, USA.
Phys Chem Chem Phys. 2024 Aug 22;26(33):22278-22285. doi: 10.1039/d4cp02331e.
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 KLVFFAE fragment (Aβ), promoted long-lived and highly beta-sheet-like domains in the peptide oligomers. Concomitantly, heparin-Aβ 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 oligomers, thus offering insights into the contrasting inhibition of fibrillation by the relatively rigid polysaccharide, chitosan.
开发了一种肝素的粗粒（CG）模型，用于研究肝素增强许多淀粉样肽纤维形成的机制。CG 分子动力学模拟表明，肝素通过与模型淀粉样肽，即淀粉样β的 KLVFFAE 片段（Aβ）形成接触，促进了肽低聚物中长寿命且高度β-折叠样结构域的形成。同时，肝素-Aβ 接触抑制了低聚物β-结构域的混合熵。这样的低聚物可以成为更好的纤维形成种子，可能导致肝素的纤维增强行为。此外，肝素柔韧性的降低导致聚集延迟和更无序的 Aβ 低聚物，从而深入了解相对刚性多糖壳聚糖对纤维形成的抑制作用。
