Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations
ABSTRACT 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 it...
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Wiley
2025-05-01
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| Online Access: | https://doi.org/10.1002/agt2.70023 |
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| author | Lulu Bi Linge Li Xiang Li Shaojuan Wu Xia Zhang Yilin Zhao Dan Li Cong Liu Zhonghuai Hou Bo Sun |
| author_facet | Lulu Bi Linge Li Xiang Li Shaojuan Wu Xia Zhang Yilin Zhao Dan Li Cong Liu Zhonghuai Hou Bo Sun |
| author_sort | Lulu Bi |
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| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-5ca7174825dc4b0782f3bb66c87a292d |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
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| spelling | doaj-art-5ca7174825dc4b0782f3bb66c87a292d2025-08-20T02:33:11ZengWileyAggregate2692-45602025-05-0165n/an/a10.1002/agt2.70023Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics SimulationsLulu Bi0Linge Li1Xiang Li2Shaojuan Wu3Xia Zhang4Yilin Zhao5Dan Li6Cong Liu7Zhonghuai Hou8Bo Sun9School of Life Science and Technology ShanghaiTech University Shanghai ChinaHefei National Research Center for Physical Sciences at the Microscale & Department of Chemical Physics University of Science and Technology of China Hefei ChinaBio‐X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) Shanghai Jiao Tong University Shanghai ChinaSchool of Life Science and Technology ShanghaiTech University Shanghai ChinaSchool of Life Science and Technology ShanghaiTech University Shanghai ChinaSchool of Life Science and Technology ShanghaiTech University Shanghai ChinaBio‐X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) Shanghai Jiao Tong University Shanghai ChinaInterdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Shanghai ChinaHefei National Research Center for Physical Sciences at the Microscale & Department of Chemical Physics University of Science and Technology of China Hefei ChinaSchool of Life Science and Technology ShanghaiTech University Shanghai ChinaABSTRACT 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.https://doi.org/10.1002/agt2.70023molecular simulationsoptical tweezersParkinson's diseasesingle moleculeα‐Syn fibril |
| spellingShingle | Lulu Bi Linge Li Xiang Li Shaojuan Wu Xia Zhang Yilin Zhao Dan Li Cong Liu Zhonghuai Hou Bo Sun Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations Aggregate molecular simulations optical tweezers Parkinson's disease single molecule α‐Syn fibril |
| title | Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations |
| title_full | Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations |
| title_fullStr | Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations |
| title_full_unstemmed | Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations |
| title_short | Bridging Mechanical Properties with Atomic Structures of Polymorphic α‐Synuclein Fibrils by Single‐Molecule Analysis and Molecular Dynamics Simulations |
| title_sort | bridging mechanical properties with atomic structures of polymorphic α synuclein fibrils by single molecule analysis and molecular dynamics simulations |
| topic | molecular simulations optical tweezers Parkinson's disease single molecule α‐Syn fibril |
| url | https://doi.org/10.1002/agt2.70023 |
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