Abstract Background Cyclin-dependent kinase 4 (CDK4) plays an essential role in cell cycle regulation, and its dysregulation has been implicated in multiple cancers. Finding harmful CDK4 mutations can help with cancer research and create tailored treatments. The CDK4 gene encodes the protein CDK4, which is a D-type cyclin binding protein that plays a vital role in the cell cycle proceeding from G1 to S phase. Result This study applied numerous computational approaches to explore single nucleotide polymorphisms (SNPs) in CDK4 . We retrieved the SNPs data of CDK4 from Variation viewer and gnomAD databases for analyzing the variants associated with cancer. With a view to retrieving SNPs data of CDK4 Variation viewer and gnomAD databases were utilized. Twenty-one nsSNPs were found to be the most deleterious or disease causing by utilizing 10 sequence-based web tools to predict the structural and functional annotation of SNPs. We used ConSurf and PROSITE web servers to predict the conservation of the CDK4 protein, which projected all 21 most detrimental nsSNPs belonging to this conserved domain with the ability to disrupt the proteins functionality. The D158Y mutant of CDK4 showed significantly less binding affinity with Cyclin D after the evaluation of molecular docking performed by the HADDOCK 2.4 server. Furthermore, Molecular dynamics simulation studies have shown that the variant may destabilize the protein structure. After examining the effects of potential mutations on post-translational modification sites and protein–protein interactions in the CDK4 protein we found the D158Y (rs2140386429) variant is identified as a potentially crucial CDK4 mutation that may be linked to cancer development based on computational predictions (Fig. 1). Thus, this variant could affect the interactions and structural stability of CDK4, providing possible targets for therapeutic intervention in malignancies driven by CDK4. Conclusion Our extensive computational investigation identifies the D158Y (rs2140386429) variation of CDK4 as a significant mutation that may modify protein structure and function, therefore playing a role in cancer etiology. This finding underscores the importance of this variant as a potential target for therapeutic strategies aimed at malignancies driven by CDK4 dysregulation.
Mazumder et al. (Fri,) studied this question.