Zhou Shuangyan, Wang Qianqian, Wang Yuwei, Yao Xiaojun, Han Wei, Liu Huanxiang
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Phys Chem Chem Phys. 2017 May 10;19(18):11249-11259. doi: 10.1039/c7cp01521f.
The structural transition of prion proteins from a native α-helix (PrP) to a misfolded β-sheet-rich conformation (PrP) is believed to be the main cause of a number of prion diseases in humans and animals. Understanding the molecular basis of misfolding and aggregation of prion proteins will be valuable for unveiling the etiology of prion diseases. However, due to the limitation of conventional experimental techniques and the heterogeneous property of oligomers, little is known about the molecular architecture of misfolded PrP and the mechanism of structural transition from PrP to PrP. The prion fragment 127-147 (PrP127-147) has been reported to be a critical region for PrP formation in Gerstmann-Straussler-Scheinker (GSS) syndrome and thus has been used as a model for the study of prion aggregation. In the present study, we employ molecular dynamics (MD) simulation techniques to study the conformational change of this fragment that could be relevant to the PrP-PrP transition. Employing extensive replica exchange molecular dynamics (REMD) and conventional MD simulations, we sample a huge number of conformations of PrP127-147. Using the Markov state model (MSM), we identify the metastable conformational states of this fragment and the kinetic network of transitions between the states. The resulting MSM reveals that disordered random-coiled conformations are the dominant structures. A key metastable folded state with typical extended β-sheet structures is identified with Pro137 being located in a turn region, consistent with a previous experimental report. Conformational analysis reveals that intrapeptide hydrophobic interaction and two key residue interactions, including Arg136-His140 and Pro137-His140, contribute a lot to the formation of ordered extended β-sheet states. However, network pathway analysis from the most populated disordered state indicates that the formation of extended β-sheet states is quite slow (at the millisecond level), as large structural rearrangement is needed from disordered states. We speculate that the formation process of the extended β-sheet folded states may represent an important event during the early formation of prion oligomers and the results of our study provide insights into the molecular details of the early stage of prion aggregation.
朊病毒蛋白从天然的α-螺旋构象（PrP）转变为富含β-折叠的错误折叠构象（PrP）被认为是人类和动物多种朊病毒疾病的主要病因。了解朊病毒蛋白错误折叠和聚集的分子基础对于揭示朊病毒疾病的病因具有重要价值。然而，由于传统实验技术的局限性以及寡聚体的异质性，人们对错误折叠的PrP的分子结构以及从PrP到PrP的结构转变机制知之甚少。据报道，朊病毒片段127 - 147（PrP127 - 147）是格斯特曼-施特劳斯勒-谢克尔综合征（GSS）中PrP形成的关键区域，因此已被用作研究朊病毒聚集的模型。在本研究中，我们采用分子动力学（MD）模拟技术来研究该片段可能与PrP - PrP转变相关的构象变化。通过广泛的副本交换分子动力学（REMD）和传统的MD模拟，我们对PrP127 - 147的大量构象进行了采样。使用马尔可夫状态模型（MSM），我们确定了该片段的亚稳态构象状态以及状态之间转变的动力学网络。所得的MSM表明无序的无规卷曲构象是主要结构。鉴定出一个具有典型延伸β-折叠结构的关键亚稳态折叠状态，其中Pro137位于一个转角区域，这与先前的实验报告一致。构象分析表明，肽内疏水相互作用以及两个关键残基相互作用，包括Arg136 - His140和Pro137 - His140，对有序延伸β-折叠状态的形成有很大贡献。然而，从最丰富的无序状态进行的网络路径分析表明，延伸β-折叠状态的形成相当缓慢（在毫秒级别），因为从无序状态需要进行大量的结构重排。我们推测延伸β-折叠折叠状态的形成过程可能代表了朊病毒寡聚体早期形成过程中的一个重要事件，并且我们的研究结果为朊病毒聚集早期阶段的分子细节提供了见解。
