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By calculating per-residue interface descriptors\u2500shape complementarity (Sc), buried surface area (Ab), and surface detail index (SDi)\u2500via a sliding window approach, we quantify structural packing and interdigitation across \u223c30,000 local interfaces. We introduce a sequence-overlap-modified RMSD (RMSDmod) metric for hierarchical clustering to robustly classify polymorphs and quantify structural diversity. Our results reveal that mature amyloid fibrils contain a mixture of tightly and loosely packed regions, with distinct interaction hot-spots characteristic to polymorph families. Clustering successfully distinguishes disease-specific topologies and tracks maturation pathways, demonstrating that ex vivo fibrils rearrange to more compact structures indicated by more buried side chains (larger Ab) and typically lowered Sc values compared to that seen in the case of in vitro produced fibrils formed over shorter time scales. This work establishes a topology- and interface-based framework that links residue-level interactions to polymorphic fibril evolution, exploring the most compacted as well as accessible and attackable regions.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01376","type":"journal-article","created":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:18:29Z","timestamp":1787509109000},"page":"11471-11490","source":"Crossref","is-referenced-by-count":0,"title":["Structural Hierarchy\nand Maturation of Amyloid Fibrils\nRevealed by Interface Descriptor Analysis"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3968-8776","authenticated-orcid":true,"given":"Ma\u0301te\u0301","family":"Sulyok-Eiler","sequence":"first","affiliation":[{"name":"ELTE Eo\u0308tvo\u0308s Lora\u0301nd University , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]},{"name":"Eo\u0308tvo\u0308s Lora\u0301nd University , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1866-9904","authenticated-orcid":true,"given":"Veronika","family":"Harmat","sequence":"additional","affiliation":[{"name":"ELTE Eo\u0308tvo\u0308s Lora\u0301nd University , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]},{"name":"Hungarian Research Network , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-6416","authenticated-orcid":true,"given":"Andra\u0301s","family":"Perczel","sequence":"additional","affiliation":[{"name":"HUN-REN Research Centre for Natural Sciences , , Magyar Tudo\u0301sok Ko\u0308ru\u0301tja 2 , ,","place":["Budapest, Hungary, H-1117"]},{"name":"ELTE Eo\u0308tvo\u0308s Lora\u0301nd University , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]},{"name":"Hungarian Research Network , , Pa\u0301zma\u0301ny P. stny. 1\/A , ,","place":["Budapest, Hungary, H-1117"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"6","key":"2026091409074907900_cit1","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1016\/j.cell.2012.02.022","article-title":"The Amyloid State of Proteins in Human Diseases","volume":"148","author":"Eisenberg","year":"2012","journal-title":"Cell"},{"issue":"4","key":"2026091409074907900_cit2","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1159\/000506696","article-title":"The Pathology\nof Amyloidosis in Classification: A Review","volume":"143","author":"Picken","year":"2020","journal-title":"Acta Haematol."},{"issue":"3","key":"2026091409074907900_cit3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.14797\/mdcj-8-3-3","article-title":"The Amyloidoses: Clinical Features, Diagnosis and Treatment","volume":"8","author":"Baker","year":"2012","journal-title":"Methodist Debakey Cardiovasc J."},{"issue":"11","key":"2026091409074907900_cit4","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1002\/pro.3275","article-title":"Amyloidogenesis of Tau Protein","volume":"26","author":"Nizynski","year":"2017","journal-title":"Protein Sci."},{"issue":"10","key":"2026091409074907900_cit5","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.3390\/biom11101419","article-title":"Structural\nand Functional Insights into \u03b1-Synuclein Fibril Polymorphism","volume":"11","author":"Mehra","year":"2021","journal-title":"Biomolecules"},{"key":"2026091409074907900_cit6","doi-asserted-by":"publisher","first-page":"4680","DOI":"10.1111\/febs.70485","article-title":"Investigating Transthyretin Variants\nH88R and I107V\nin Amyloid Priming: From Destabilization to Complete Dissociation","volume":"293","author":"Bo\u0301dy","year":"2026","journal-title":"FEBS J."},{"issue":"1","key":"2026091409074907900_cit7","doi-asserted-by":"publisher","first-page":"16809","DOI":"10.1038\/s41598-017-16953-7","article-title":"Concurrent Structural\nand Biophysical Traits Link with Immunoglobulin Light Chains Amyloid\nPropensity","volume":"7","author":"Oberti","year":"2017","journal-title":"Sci. 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