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AuthorMuhammad, Suleman
AuthorKhattak, Aishma
AuthorAkbar, Fazal
AuthorRizwan, Muhammad
AuthorTayyab, Muhammad
AuthorYousaf, Muhammad
AuthorKhan, Abbas
AuthorAlbekairi, Norah A.
AuthorAgouni, Abdelali
AuthorCrovella, Sergio
Available date2024-01-28T10:33:56Z
Publication Date2024-03-31
Publication NameInternational Journal of Biological Macromolecules
Identifierhttp://dx.doi.org/10.1016/j.ijbiomac.2024.129559
ISSN01418130
URIhttps://www.sciencedirect.com/science/article/pii/S0141813024003623
URIhttp://hdl.handle.net/10576/51236
AbstractCancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of −242 kcal/mol for wild-type, while the mutant complexes had scores ranging from −217 to −220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was −64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were −45.90 kcal/mol, −53.52 kcal/mol, −55.67 kcal/mol, and −61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.
SponsorThis work was supported by Qatar University grant No. QUPD-CAS-23-24-491.
Languageen
PublisherElsevier
SubjectE2F1
SNPs
Molecular simulation
TitleAnalysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer
TypeArticle
Volume Number260
dc.accessType Full Text


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