Computational screening and structural analysis of Gly201Arg and Gly201Asp missense mutations in human cyclin-dependent kinase 4 protein.

Abstract

The regulatory proteins, cyclins, and cyclin-dependent kinases (CDKs) control the cell cycle progression. CDK4 gene mutations are associated with certain cancers such as melanoma, breast cancer, and rhabdomyosarcoma. Therefore, understanding the mechanisms of cell cycle control and cell proliferation is essential in developing cancer treatment regimens. In this study, we obtained cancer-causing CDK4 mutations from the COSMIC database and subjected them to a series of in silico analyses to identify the most significant mutations. An overall of 238 mutations (119 missense mutations) retrieved from the COSMIC database were investigated for the pathogenic and destabilizing properties using the PredictSNP and iStable algorithms. Further, the amino acid position of the most pathogenic and destabilizing mutations were analyzed to understand the nature of amino acid conservation across the species during the evolution. We observed that the missense mutations G201R and G201D were more significant and the Glycine at position 201 was found to highly conserved. These significant mutations were subjected to molecular dynamics simulation analysis to understand the protein's structural changes. The results from molecular dynamics simulations revealed that both G201R and G201D of CDK4 are capable of altering the protein's native form. On comparison among the most significant mutations, G201R disrupted the protein structure higher than the protein with G201D.