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Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular level

2024-03-26Journal article Open access
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dc.contributor.authorPeixoto, Vanda
dc.contributor.authorPrudêncio, Cristina
dc.contributor.authorVieira, Mónica
dc.contributor.authorSousa, Sérgio F.
dc.date.accessioned2024-05-28T11:49:39Z
dc.date.embargo2025-03-26
dc.date.issued2024-03-26
dc.description.abstractComplement C5 is the target of the monoclonal antibody eculizumab, used in complement dysregulating disorders, like the rare disease Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired hematopoietic stem cell condition characterized by aberrant destruction of erythrocytes, chronic hemolytic anemia, and thromboembolism propensity. C5 is a protein component of the complement system which is part of the immune system of the body and plays a prominent role in the destruction of red blood cells, misidentifying them as a threat. This work describes the application of molecular dynamics simulations to the study of the underlying interactions between complement C5 and eculizumab. This study also reveals the importance of single nucleotide polymorphisms on C5 protein concerning the effective inhibition of the mAB, involving the mechanistic events taking place at the interface spots of the complex. The predicted conformational change in the C5 Arg885/His/Cys mutation has implications on the protein’s interaction with eculizumab, compromising their compatibility. The acquired insights into the conformational changes, dynamics, flexibility, and interactions shed light on the knowledge of the function of this biomolecule providing answers about the poor response to the treatment in PNH patient carriers of the mutations. By investigating the intricate dynamics, significant connections between C5 and eculizumab can be uncovered. Such insights may aid in the creation of novel compounds or lead to the enhancement of eculizumab’s efficacy.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPeixoto, V. P., Prudêncio, C., Vieira, M., & Sousa, S. F. (2024). Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular level. Journal of Biomolecular Structure and Dynamics, 0(0), 1–10. https://doi.org/10.1080/07391102.2024.2331091pt_PT
dc.identifier.doi10.1080/07391102.2024.2331091pt_PT
dc.identifier.eissn1538-0254
dc.identifier.issn0739-1102
dc.identifier.urihttp://hdl.handle.net/10400.22/25579
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherTaylor & Francispt_PT
dc.relationThis work was financially supported with funding from FCT/MCTES (UIDP/50006/2020) through national funds. Some of the calculations were produced with the support of INCD funded by FCT and FEDER under project 01/SAICT/2016 number 022153 and projects CPCA/A00/ 7140/2020, CPCA/A00/7145/2020, and 2021.09752.CPCA. SFS acknowledges FCT for funding through program 2020.01423.CEECIND.pt_PT
dc.relation.publisherversionhttps://www.tandfonline.com/doi/full/10.1080/07391102.2024.2331091pt_PT
dc.subjectComputational simulationpt_PT
dc.subjectEculizumabpt_PT
dc.subjectComplement C5pt_PT
dc.subjectGenetic polymorphismspt_PT
dc.subjectStructural analysispt_PT
dc.titleEvaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular levelpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage10pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleJournal of Biomolecular Structure and Dynamics (JBSD)pt_PT
person.familyNamePeixoto
person.familyNamePrudêncio
person.familyNameAlmeida Vieira
person.givenNameVanda
person.givenNameCristina
person.givenNameMónica Andreia
person.identifier1200571
person.identifier.ciencia-idC81E-F4EE-FADE
person.identifier.ciencia-idA01E-9178-9B48
person.identifier.orcid0000-0003-4883-3186
person.identifier.orcid0000-0002-9920-936X
person.identifier.orcid0000-0002-8687-4811
person.identifier.scopus-author-id6508057930
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationaf5cb379-3640-49bc-9d0a-43dd212821a1
relation.isAuthorOfPublication881a8ad5-ab13-4e49-89f4-08ca61cc81e3
relation.isAuthorOfPublication861e9c68-4ecc-4be1-a794-852343368e9a
relation.isAuthorOfPublication.latestForDiscovery861e9c68-4ecc-4be1-a794-852343368e9a

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