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Computational screening and structural analysis of Gly201Arg and Gly201Asp missense mutations in human
D Thirumal Kumar1, Nishaat Shaikh2, R Bithia3
1Faculty of Allied Health Sciences, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India.
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.
Insights
Cancer-associated CDK4 mutations, particularly G201R and G201D, significantly alter protein structure. Understanding these cell cycle regulator changes is crucial for developing targeted cancer therapies.
Area of Science:
- Molecular Biology
- Genetics
- Computational Biology
Background:
- Cell cycle progression is regulated by proteins like cyclins and cyclin-dependent kinases (CDKs).
- Mutations in the CDK4 gene are linked to various cancers, including melanoma, breast cancer, and rhabdomyosarcoma.
- Understanding CDK4's role in cell proliferation is vital for cancer treatment development.
Purpose of the Study:
- To identify significant cancer-causing mutations in the CDK4 gene.
- To analyze the pathogenic and structural impact of these mutations using in silico methods.
- To investigate the evolutionary conservation of affected amino acid residues.
Main Methods:
- Retrieved 238 CDK4 mutations (119 missense) from the COSMIC database.
- Utilized PredictSNP and iStable algorithms to assess mutation pathogenicity and destabilization.
- Performed molecular dynamics simulations to analyze structural changes induced by significant mutations.
Main Results:
- Identified G201R and G201D as significant missense mutations in CDK4.
- Found that Glycine at position 201 is highly conserved across species.
- Molecular dynamics simulations showed G201R and G201D alter CDK4's native structure, with G201R causing greater disruption.
Conclusions:
- Specific CDK4 mutations, G201R and G201D, demonstrably alter protein structure.
- The high conservation of Glycine at position 201 highlights its functional importance.
- These findings provide insights into CDK4's role in cancer and potential therapeutic targets.
