Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR
Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR
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多尺度分子动力学模拟、马尔可夫态模型和 NMR 揭示了 a-突触核蛋白的膜相互作用
DOI：
10.1101/2020.06.18.156216
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Amos S
中科院分区：
文献类型：
--
作者：
Amos S
α-突触核蛋白（αS）是一种突触前蛋白，与细胞膜结合，与帕金森病（PD）有关。αS与膜的结合可能是PD分子病理生理学的第一步。αS分子可以采用多种构象，在水中基本上是无序的，当存在于淀粉样蛋白纤维中时采用β-折叠构象，并且当结合到脂质双层和相关的膜模拟表面时形成动态多样的α-螺旋构象。多尺度分子动力学模拟结合核磁共振（NMR）和交联质谱（XLMS）测量被用于探索αS与阴离子脂质双层的相互作用。模拟和NMR测量共同揭示了αS的中心非淀粉样蛋白-β组分（NAC）区域的螺旋结构在残基65-70附近的断裂，这可能有助于随后的寡聚体形成。从αS与去污剂胶束结合时的结构开始对αS进行粗粒度模拟，揭示了蛋白质与阴离子脂质双层接触的总体模式，而随后的全原子模拟提供了膜结合后构象变化的细节。特别是，脂质体结合的αS的模拟和NMR数据表明NAC区域中的初始β链形成，这得到了分子内接触seenviaXLMS和模拟的支持。基于全原子模拟的Markov态模型提出了膜结合αSviaa构象变化的机制，即NAC区65位残基的动态螺旋断裂。膜相互作用αS的涌现动力学模型推进了我们对PD机制的理解，可能有助于设计新的治疗方法。
α-Synuclein (αS) is a presynaptic protein that binds to cell membranes and is linked to Parkinson’s disease (PD). Binding of αS to membranes is a likely first step in the molecular pathophysiology of PD. The αS molecule can adopt multiple conformations, being largely disordered in water, adopting a β-sheet conformation when present in amyloid fibrils, and forming a dynamic multiplicity of α-helical conformations when bound to lipid bilayers and related membrane-mimetic surfaces. Multiscale molecular dynamics simulations in conjunction with nuclear magnetic resonance (NMR) and cross-linking mass spectrometry (XLMS) measurements are used to explore the interactions of αS with an anionic lipid bilayer. The simulations and NMR measurements together reveal a break in the helical structure of the central non-amyloid-β component (NAC) region of αS in the vicinity of residues 65–70, which may facilitate subsequent oligomer formation. Coarse-grained simulations of αS starting from the structure of αS when bound to a detergent micelle reveal the overall pattern of protein contacts to anionic lipid bilayers, while subsequent all-atom simulations provide details of conformational changes upon membrane binding. In particular, simulations and NMR data for liposome-bound αS indicate incipient β-strand formation in the NAC region, which is supported by intramolecular contacts seenviaXLMS and simulations. Markov state models based on the all-atom simulations suggest a mechanism of conformational change of membrane-bound αSviaa dynamic helix break in the region of residue 65 in the NAC region. The emergent dynamic model of membrane-interacting αS advances our understanding of the mechanism of PD, potentially aiding the design of novel therapeutic approaches.