A Multiscale Approach to Characterize the Early Aggregation Steps of the Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35

The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided.

肽自组装形成淀粉样蛋白寡聚体(amyloidogenic oligomer)，是众多分子疾病与退行性疾病发生发展的关键事件之一。因此，对聚集过程的作用机制及其最终形成的结构开展原子分辨率层面的表征，是深化我们对这类疾病致病决定因素认知的必要环节。为解决这一问题，本研究将基于OPEP粗粒化势能(OPEP coarse-grained potential)的副本交换分子动力学模拟(replica exchange molecular dynamics)的加速采样特性，与全原子分子动力学模拟(all-atom molecular dynamics simulation)所提供的相互作用原子分辨率描述相结合，并针对3聚体、12聚体与20聚体三种体系尺寸，探究GNNQQNY肽的寡聚化过程。我们的整合模拟结果显示，各尺寸的聚集体均存在丰富多样的结构排布形式。在20聚体体系中，可瞬时形成细长的纤维状结构，但这类结构并不稳定，且易于转化为更为球状且无序的聚集体形式。我们对中间结构及其理化决定因素的全面表征表明，GNNQQNY序列存在高度的结构多态性，且该特性可在宏观尺度上得以体现。本研究同时阐明了淀粉样蛋白聚集背后的具体作用机制与相关结构。