探索生理 C 端截短对α-突触核蛋白构象的影响,揭示调节病理聚集的机制。

IF 5.6 2区 化学 Q1 CHEMISTRY, MEDICINAL Journal of Chemical Information and Modeling Pub Date : 2024-11-25 Epub Date: 2024-11-06 DOI:10.1021/acs.jcim.4c01839
Fengjuan Huang, Jiajia Yan, Huan Xu, Ying Wang, Xiaohan Zhang, Yu Zou, Jiangfang Lian, Feng Ding, Yunxiang Sun
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引用次数: 0

摘要

新的证据表明,α-突触核蛋白(αS)的生理性 C 端截断在调节液-液相分离和促进淀粉样蛋白聚集方面起着关键作用,而这些过程与帕金森病(PD)等神经退行性疾病有关。然而,人们对 C 端截短影响 αS 构象并调节其聚集的分子机制仍然知之甚少。在这项研究中,我们通过原子离散分子动力学模拟比较了全长αS1-140和截短的αS1-103单体,研究了C端截短对αS构象动力学的影响。我们的研究结果表明,αS1-140 和 αS1-103主要围绕残基 7-32 采用螺旋构象,而位于 N 端和 NAC 结构域后半部的残基 36-95 则主要形成动态的 β 片状核心。αS1-140 的 C 端在很大程度上是非结构化的,并动态地包裹在 β 片状核心周围。虽然残基 1-95 在 αS1-140 和 αS1-103 中表现出相似的二级结构倾向性,但 αS1-140 中 C 端的动态封顶略微增强了残基 36-95 周围的 β 片层形成。与此相反,αS1-140 中的 C 端动态屏蔽了关键的聚集驱动区(残基 2-9、36-42、45-57 和 68-78),减少了它们的暴露,并有可能防止肽间相互作用导致聚集。另一方面,C端截短增加了这些易聚集区域的暴露表面积,从而增强了肽间相互作用、相分离和淀粉样蛋白聚集。总之,我们的模拟为了解 C 端截短对αS 的构象效应及其在促进病理聚集中的作用提供了宝贵的见解。
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Exploring the Impact of Physiological C-Terminal Truncation on α-Synuclein Conformations to Unveil Mechanisms Regulating Pathological Aggregation.

Emerging evidence suggests that physiological C-terminal truncation of α-synuclein (αS) plays a critical role in regulating liquid-liquid phase separation and promoting amyloid aggregation, processes implicated in neurodegenerative diseases such as Parkinson's disease (PD). However, the molecular mechanisms through which C-terminal truncation influences αS conformation and modulates its aggregation remain poorly understood. In this study, we investigated the impact of C-terminal truncation on αS conformational dynamics by comparing full-length αS1-140 with truncated αS1-103 monomers using atomistic discrete molecular dynamics simulations. Our findings revealed that both αS1-140 and αS1-103 primarily adopted helical conformations around residues 7-32, while residues 36-95, located in the second half of the N-terminal and NAC domains, predominantly formed a dynamic β-sheet core. The C-terminus of αS1-140 was largely unstructured and dynamically wrapped around the β-sheet core. While residues 1-95 exhibited similar secondary structure propensities in both αS1-140 and αS1-103, the dynamic capping by the C-terminus in αS1-140 slightly enhanced β-sheet formation around residues 36-95. In contrast, key aggregation-driving regions (residues 2-9, 36-42, 45-57, and 68-78) were dynamically shielded by the C-terminus in αS1-140, reducing their exposure and potentially preventing interpeptide interactions that drive aggregation. C-terminal truncation, on the other hand, increased the exposed surface area of these aggregation-prone regions, thereby enhancing interpeptide interactions, phase separation, and amyloid aggregation. Overall, our simulations provide valuable insights into the conformational effects of C-terminal truncation on αS and its role in promoting pathological aggregation.

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CiteScore
9.80
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10.70%
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529
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期刊介绍: The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.
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