{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:43:40Z","timestamp":1760402620649,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"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":["UIDB\/04046\/2020, UIDP\/04046\/2020 (to BioISI), PTDC\/NEU-NMC\/2138\/2014 (CG), PTDC\/FIS-OUT\/28210\/2017 and CEECIND\/02300\/2017 (to MM)."],"award-info":[{"award-number":["UIDB\/04046\/2020, UIDP\/04046\/2020 (to BioISI), PTDC\/NEU-NMC\/2138\/2014 (CG), PTDC\/FIS-OUT\/28210\/2017 and CEECIND\/02300\/2017 (to MM)."]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>S100B is an astrocytic extracellular Ca2+-binding protein implicated in Alzheimer\u2019s disease, whose role as a holdase-type chaperone delaying A\u03b242 aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and A\u03b242. Driven by previous structural data, we used the A\u03b225\u201335 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length A\u03b2 using long (1 \u03bcs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, A\u03b2-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(A\u03b2)\/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over A\u03b2 aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the A\u03b2-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ijms22073629","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T10:24:33Z","timestamp":1617186273000},"page":"3629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid \u03b2 Peptide Client"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2795-9866","authenticated-orcid":false,"given":"Filipe E. P.","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-9335","authenticated-orcid":false,"given":"Ant\u00f3nio J.","family":"Figueira","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-6933","authenticated-orcid":false,"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-8744","authenticated-orcid":false,"given":"Miguel","family":"Machuqueiro","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fnins.2017.00185","article-title":"Protein Quality Control by Molecular Chaperones in Neurodegeneration","volume":"11","author":"Ciechanover","year":"2017","journal-title":"Front. 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