{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:21:25Z","timestamp":1772252485160,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T00:00:00Z","timestamp":1572912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER family that is overexpressed in some of the most aggressive tumours. Although it is known that HER2 dimerization involves a specific region of its extracellular domain, the so-called \u201cdimerization arm\u201d, the mechanism of dimerization inhibition remains uncertain. However, uncovering how antibody interactions lead to inhibition of HER2 dimerization is of key importance in understanding its role in tumour progression and therapy. Herein, we employed several computational modelling techniques for a molecular-level understanding of the interactions between HER and specific anti-HER2 antibodies, namely an antigen-binding (Fab) fragment (F0178) and a single-chain variable fragment from Trastuzumab (scFv). Specifically, we investigated the effects of antibody-HER2 interactions on the key residues of \u201cdimerization arm\u201d from molecular dynamics (MD) simulations of unbound HER (in a total of 1 \u00b5s), as well as ScFv:HER2 and F0178:HER2 complexes (for a total of 2.5 \u00b5s). A deep surface analysis of HER receptor revealed that the binding of specific anti-HER2 antibodies induced conformational changes both in the interfacial residues, which was expected, and in the ECDII (extracellular domain), in particular at the \u201cdimerization arm\u201d, which is critical in establishing protein\u2013protein interface (PPI) interactions. Our results support and advance the knowledge on the already described trastuzumab effect on blocking HER2 dimerization through synergistic inhibition and\/or steric hindrance. Furthermore, our approach offers a new strategy for fine-tuning target activity through allosteric ligands.<\/jats:p>","DOI":"10.3390\/biom9110706","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T02:48:31Z","timestamp":1573094911000},"page":"706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dynamical Rearrangement of Human Epidermal Growth Factor Receptor 2 upon Antibody Binding: Effects on the Dimerization"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4118-2800","authenticated-orcid":false,"given":"Pedro","family":"R. Magalh\u00e3es","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica e Bioqu\u00edmica 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":"Centro de Qu\u00edmica e Bioqu\u00edmica and Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1887-0157","authenticated-orcid":false,"given":"Jos\u00e9","family":"G. Almeida","sequence":"additional","affiliation":[{"name":"European Bioinformatics Institute, Cambridge CB10 1SD, UK"}]},{"given":"Andr\u00e9","family":"Melo","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Faculdade de Ci\u00eancias da Universidade do Porto, Departamento de Qu\u00edmica e Bioqu\u00edmica, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3375-8670","authenticated-orcid":false,"given":"M. Nat\u00e1lia","family":"D. S. Cordeiro","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Faculdade de Ci\u00eancias da Universidade do Porto, Departamento de Qu\u00edmica e Bioqu\u00edmica, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6615-5289","authenticated-orcid":false,"given":"Sandra","family":"Cabo Verde","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares and Departamento de Engenharia e Ci\u00eancias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-2202","authenticated-orcid":false,"given":"Zeynep","family":"H. G\u00fcm\u00fc\u015f","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2970-5250","authenticated-orcid":false,"given":"Irina","family":"S. Moreira","sequence":"additional","affiliation":[{"name":"DDMD\u2013Data Driven Molecular Design Group, CNC - Center for Neuroscience and Cell Biology. University of Coimbra, UC Biotech Building, Nucleus 4, Lot 3, Biocant Park, 3060-197 Cantanhede, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-4906","authenticated-orcid":false,"given":"Jo\u00e3o","family":"D. G. Correia","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares and Departamento de Engenharia e Ci\u00eancias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1056-1007","authenticated-orcid":false,"given":"Rita","family":"Melo","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares and Departamento de Engenharia e Ci\u00eancias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal"},{"name":"DDMD\u2013Data Driven Molecular Design Group, CNC - Center for Neuroscience and Cell Biology. 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