School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia.
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
ACS Chem Neurosci. 2024 Feb 21;15(4):716-723. doi: 10.1021/acschemneuro.3c00754. Epub 2024 Jan 18.
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.
多肽和蛋白质自组装成富含β-折叠的淀粉样纤维与功能和病理状态都有关联。在这项研究中，研究了来自酵母朊病毒 Sup35 蛋白的短肽 GNNQQNY 的纤维状结构的生长。分子动力学模拟用于研究纤维生长的替代机制，包括通过单体的结合进行延伸以及纤维自身组装成更大、更成熟的结构。结果发现，单体结合后沿着预先形成的纤维向末端扩散，支持通过延伸来促进纤维生长的机制。原纤维的侧向组装被发现很容易发生，这表明这可能是从孤立的纤维过渡到成熟的多层结构的关键。总的来说，这项工作为控制淀粉样纤维生长的竞争途径提供了机制上的见解。
