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AuthorThirumal Kumar, D
AuthorMendonca, Enid
AuthorPriyadharshini Christy, J
AuthorGeorge Priya Doss, C
AuthorZayed, Hatem
Available date2019-03-05T10:22:49Z
Publication Date2019-02-26
Publication NameAdvances in Protein Chemistry and Structural Biologyen_US
Identifierhttp://dx.doi.org/10.1016/bs.apcsb.2018.11.006
CitationThirumal Kumar D, Mendonca E, Priyadharshini Christy J, George Priya Doss C, Zayed H. A computational model to predict the structural and functional consequences of missense mutations in O(6)-methylguanine DNA methyltransferase. Adv Protein Chem Struct Biol. 2019;115:351-369. doi: 10.1016/bs.apcsb.2018.11.006.
ISSN1876-1623
URIhttp://hdl.handle.net/10576/11370
AbstractDNA repair mechanism is a process through which the cell repairs its damaged DNA. Although there are several mechanisms involved in the DNA repair mechanisms, the direct reversal method is the simplest and does not require a reference template, in which the guanine bases are often methylated, and the methyl guanine methyl transferase protein (MGMT) reverses them. The mutations occurring in the MGMT protein might result in dysfunction of such DNA repair mechanism. In this study, we attempted to evaluate the impact of six missense mutations (Y114E, Y114A, R128G, R128A, R128K, and C145A) at three active-site positions (Y114, C145, and R128) as this might hinder the DNA binding to the protein. These six mutations were subjected to pathogenicity, stability, and conservation analysis using online servers such as PredictSNP, iStable, and ConSurf, respectively. From the predictions, all the six mutations were almost predicted to be significant. Considering true positives, true negatives, false positives, and false negatives, three mutations (Y114E, R128G, and C145A) showed "loss of DNA repair activity," and were analyzed further using molecular dynamics simulations (MDS) using GROMACS for 50ns. MDS run showed that the C145A mutant demonstrated higher structural deviation, decreased compactness, and the binding patterns. The Y114E mutant showed almost a null effect from the structural analysis. Finally, the R128G mutant showed structural variations in between the C145A and Y114E mutations of MGMT protein. We believe that the observed findings in this computational approach might further pave a way of providing better treatment measures by understanding the DNA repair mechanisms.
Languageen
PublisherElsevier
SubjectDNA repair
SubjectIn silico predictors
SubjectMGMT
SubjectMindist
SubjectMissense mutations
SubjectMolecular dynamics simulations
TitleA computational model to predict the structural and functional consequences of missense mutations in O-methylguanine DNA methyltransferase.
TypeArticle
Pagination351-369
Volume Number115
dc.identifier.essn 1876-1631


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