{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:46:16Z","timestamp":1778636776209,"version":"3.51.4"},"reference-count":92,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T00:00:00Z","timestamp":1565740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/FIS-OUT\/28210\/2017; UID\/MULTI\/04046\/2019; PD\/BD\/108259\/2015"],"award-info":[{"award-number":["PTDC\/FIS-OUT\/28210\/2017; UID\/MULTI\/04046\/2019; PD\/BD\/108259\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Human \u03b22-microglobulin (b2m) protein is classically associated with dialysis-related amyloidosis (DRA). Recently, the single point mutant D76N was identified as the causative agent of a hereditary systemic amyloidosis affecting visceral organs. To get insight into the early stage of the \u03b22m aggregation mechanism, we used molecular simulations to perform an in depth comparative analysis of the dimerization phase of the D76N mutant and the \u0394N6 variant, a cleaved form lacking the first six N-terminal residues, which is a major component of ex vivo amyloid plaques from DRA patients. We also provide first glimpses into the tetramerization phase of D76N at physiological pH. Results from extensive protein\u2013protein docking simulations predict an essential role of the C- and N-terminal regions (both variants), as well as of the BC-loop (\u0394N6 variant), DE-loop (both variants) and EF-loop (D76N mutant) in dimerization. The terminal regions are more relevant under acidic conditions while the BC-, DE- and EF-loops gain importance at physiological pH. Our results recapitulate experimental evidence according to which Tyr10 (A-strand), Phe30 and His31 (BC-loop), Trp60 and Phe62 (DE-loop) and Arg97 (C-terminus) act as dimerization hot-spots, and further predict the occurrence of novel residues with the ability to nucleate dimerization, namely Lys-75 (EF-loop) and Trp-95 (C-terminus). We propose that D76N tetramerization is mainly driven by the self-association of dimers via the N-terminus and DE-loop, and identify Arg3 (N-terminus), Tyr10, Phe56 (D-strand) and Trp60 as potential tetramerization hot-spots.<\/jats:p>","DOI":"10.3390\/biom9080366","type":"journal-article","created":{"date-parts":[[2019,8,15]],"date-time":"2019-08-15T04:22:54Z","timestamp":1565842974000},"page":"366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Early Phase of \u03b22m Aggregation: An Integrative Computational Study Framed on the D76N Mutant and the \u0394N6 Variant"],"prefix":"10.3390","volume":"9","author":[{"given":"Rui","family":"J. S. Loureiro","sequence":"first","affiliation":[{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"given":"Diogo","family":"Vila-Vi\u00e7osa","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute and Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-8744","authenticated-orcid":false,"given":"Miguel","family":"Machuqueiro","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute and Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"given":"Eugene I.","family":"Shakhnovich","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-2748","authenticated-orcid":false,"given":"Patr\u00edcia","family":"F. N. Fa\u00edsca","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute and Departamento de F\u00edsica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1134\/S0006297914130057","article-title":"Mechanisms of amyloid fibril formation","volume":"79","author":"Dovidchenko","year":"2014","journal-title":"Biochem. Biokhimiia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding, functional amyloid, and human disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Harris, J.R. (2012). 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