Bridging mechanical properties with atomic structures of polymorphic α-synuclein fibrils by single-molecule analysis and molecular dynamics simulations

doi:10.1002/agt2.70023

	Bridging mechanical properties with atomic structures of polymorphic α-synuclein fibrils by single-molecule analysis and molecular dynamics simulations
	Bi, Lulu1,2 ; Li, Linge 3; Li, Xiang 4,5; Wu, Shaojuan1 ; Zhang, Xia1 ; Zhao, Yilin1 ; Li, Dan 4,5; Liu, Cong 6,7,8; Hou, Zhonghuai 3; Sun, Bo1
	2025-03-13
发表期刊	AGGREGATE (IF:13.9[JCR-2023],14.9[5-Year])
ISSN	2692-4560
EISSN	2692-4560
卷号	6 页码:e70023
发表状态	已发表
DOI	10.1002/agt2.70023
摘要	α-Synuclein (α-syn) forms structurally distinct fibril polymorphs with various pathological activities in different subtypes of synucleinopathies, such as Parkinson's disease (PD). As a unique proteinaceous polymer, the mechanical property of α-syn fibril is a primary determinant of its neurotoxicity, immunogenicity, and seeding and transmission capacity. Nevertheless, how genetic mutations in α-syn fibrils cause varied polymer behaviors remains largely unknown. Using optical tweezers, we quantitatively characterize the mechanical properties of three α-syn fibril variants at the single-molecule level. We find that wild-type α-syn fibrils are generally more sustainable to an axial disruption force than those formed by the disease-causing E46K and A53T α-syn mutants, whereas their heterogeneous elastic properties manifest similarity. Based on the molecular dynamics simulations, the β-sheet motif and the interface between the two protofilaments dominate in stabilizing the fibril structure. Additionally, single-molecule and simulation analysis consistently reveal the force-driven α-syn protein unfolding without a fibril break. Due to the flexible periphery, these subtle structural changes become more pronounced with the E46K fibril. The structure–mechanics relationship of α-syn fibrils built in this work sheds new light on the fibril assembly and disassembly mechanism and the mutant-associated pathogenesis in PD. © 2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.
关键词	Crystal atomic structure Molecular docking Molecular dynamics Neurodegenerative diseases Dynamics simulation Mechanical Molecular simulations Optical- Parkinson's disease Property Single molecule Single-molecule analysis Α-syn fibril α-synuclein
收录类别	EI
语种	英语
出版者	John Wiley and Sons Inc
EI入藏号	20251218086385
EI主题词	Optical tweezers
EI分类号	102.1.2 Health Science - 744.6 Laser Applications - 801.3 Physical Chemistry - 1106.1 Computer Programming - 1301.1.3 Atomic and Molecular Physics - 1301.4.1.1 Crystal Lattice
原始文献类型	Article in Press
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/490286
专题	生命科学与技术学院_PI研究组_孙博组生命科学与技术学院_硕士生生命科学与技术学院_博士生
共同第一作者	Li, Linge; Li, Xiang
通讯作者	Liu, Cong; Hou, Zhonghuai; Sun, Bo
作者单位	1.School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China 2.Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China 3.Hefei National Research Center for Physical Sciences at the Microscale & Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China 4.Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China 5.Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China 6.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China 7.State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China 8.Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Bi, Lulu,Li, Linge,Li, Xiang,et al. Bridging mechanical properties with atomic structures of polymorphic α-synuclein fibrils by single-molecule analysis and molecular dynamics simulations[J]. AGGREGATE,2025,6:e70023.
APA	Bi, Lulu.,Li, Linge.,Li, Xiang.,Wu, Shaojuan.,Zhang, Xia.,...&Sun, Bo.(2025).Bridging mechanical properties with atomic structures of polymorphic α-synuclein fibrils by single-molecule analysis and molecular dynamics simulations.AGGREGATE,6,e70023.
MLA	Bi, Lulu,et al."Bridging mechanical properties with atomic structures of polymorphic α-synuclein fibrils by single-molecule analysis and molecular dynamics simulations".AGGREGATE 6(2025):e70023.