Computational insights into substrate-assisted citrullination mechanisms of PAD2 isozyme: A comparative analysis of reaction pathways

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dc.authorid0000-0001-9430-4096
dc.authorid0000-0003-4805-2988
dc.authorid0000-0001-9430-4096
dc.authorid0000-0002-3378-3481
dc.authorid0000-0002-4696-4003
dc.authorid0000-0002-6311-1918
dc.authorid0000-0003-3245-742X
dc.contributor.authorCicek, Erdem
dc.contributor.authorMunar, Ipek
dc.contributor.authorCinar, Sesil Agopcan
dc.contributor.authorBasceken, Sinan
dc.contributor.authorMonard, Gerald
dc.contributor.authorAviyente, Viktorya
dc.contributor.authorSungur, Fethiye Aylin
dc.date.accessioned2026-04-04T18:55:35Z
dc.date.available2026-04-04T18:55:35Z
dc.date.issued2025
dc.departmentİstanbul Bilgi Üniversitesi
dc.description.abstractCitrullination, catalyzed by protein arginine deiminase enzymes, involves the conversion of peptidyl-arginine to peptidyl-citrulline, disrupting protein interactions and leading to functional alterations. Despite the experimental studies on PAD2 indicating calcium dependence and substrate specificity, the catalytic mechanism remains contentious, with conflicting evidence regarding the roles of active site residues such as Cys647 and His471. The present study is an expansion of prior molecular dynamics simulations that investigated the dynamics of the enzyme PAD2, which indicated that Asp473 may function as a general acid/base, thereby challenging the experimentally proposed pathways. To further elucidate this controversial issue, quantum mechanical methods were employed to examine the protonation states of key residues and their roles in catalysis. Herein, three different pathways have been studied for the substrate-assisted citrullination mechanism of PAD2 isozyme using a model structure that includes the active site residues Asp351, His471, Val472, Asp473, and Cys647 and a water molecule. The highest barriers for two of the designed mechanisms, RM1 and RM3 are comparable: the choice of a single mechanism is not possible since the differences in barriers fall within the error margins in DFT calculations. These findings offer insights into PAD2's enzymatic activity, thereby advancing our understanding of its biological significance.
dc.description.sponsorshipTUBITAK 1001 The Scientific and Technological Research Projects Funding Program [115Z860]; National Center for High Performance Computing of Turkey (UHeM) [5005122018]
dc.description.sponsorshipThe authors thank the TUBITAK 1001 The Scientific and Technological Research Projects Funding Program (Project no: 115Z860) . Computing resources used in this work were provided by the National Center for High Performance Computing of Turkey (UHeM) under grant number 5005122018.
dc.identifier.doi10.1016/j.jmgm.2025.109107
dc.identifier.doi10.1016/j.jmgm.2025.109107
dc.identifier.issn1093-3263
dc.identifier.issn1873-4243
dc.identifier.pmid40494019
dc.identifier.scopus2-s2.0-105007472337
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.jmgm.2025.109107
dc.identifier.urihttps://hdl.handle.net/11411/10462
dc.identifier.volume140
dc.identifier.wosWOS:001507606900001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.ispartofJournal of Molecular Graphics & Modelling
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20260402
dc.snmzKA_Scopus_20260402
dc.subjectActive-Site Cysteine
dc.subjectArginine Deiminase
dc.subjectInhibition
dc.subjectCatalysis
dc.subjectStates
dc.titleComputational insights into substrate-assisted citrullination mechanisms of PAD2 isozyme: A comparative analysis of reaction pathways
dc.typeArticle

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