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Several small molecules are found to bind or dissolve \u03b1\u2010syn fibrils, offering potential therapeutic applications. Here, an innovative optical tweezers\u2010based, fluorescence\u2010combined approach is developed to probe the mechanical characteristics of \u03b1\u2010syn fibrils at the single\u2010molecule level. When subjected to axial stretching, local deformation within \u03b1\u2010syn fibrils appeared at forces above 50 pN. These structural alternations occurred stepwise and are irreversible, suggesting unfolding of individual \u03b1\u2010syn molecules or subdomains. Additionally, \u03b1\u2010syn fibrils exhibits high heterogeneity in lateral disruption, with rupture force ranging from 50 to 500 pN. The impact of different compounds on the structure and mechanical features of \u03b1\u2010syn fibrils is further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates the rupture force of fibrils by wedging into the N\u2010terminal polar groove and induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches to four different sites wrapping around the fibril core, reinforcing the stability of the fibril against rupture forces. The work offers an effective method for characterizing single\u2010fibril properties and bridges compound\u2010induced structural alternations with mechanical response. These insights are valuable for understanding amyloid fibril mechanics and their regulation by small molecules.<\/jats:p>","DOI":"10.1002\/advs.202416721","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:20:21Z","timestamp":1739532021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Single\u2010Molecule Insight Into \u03b1\u2010Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7889-0240","authenticated-orcid":false,"given":"Xiang","family":"Li","sequence":"first","affiliation":[{"name":"Bio\u2010X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) Shanghai Jiao Tong University  Shanghai 200030 China"},{"name":"Zhangjiang Institute for Advanced Study Shanghai Jiao Tong University  Shanghai 201203 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