Structural analysis of the impact of germline mutations of p16 in melanoma prone families.

Abstract

Cyclin-dependent kinases (CDKs), play essential roles in cell cycle progression. CDK activity is controlled through phosphorylation and inhibition by CDK inhibitors, such as p16. Mutations in p16 can lead to diseases such as cancer. This study examines a series of p16 mutants and their molecular interactions with CDK4 using modelling, molecular dynamics simulations, and docking studies. Despite no significant structural changes in p16 due to mutation, the binding affinity was found to be affected, correlating with conservation scales. Simulations revealed that specific mutations, such as G23D, P114S, and A60V resulted in loss of binding to CDK4, while others like R24Q and G67R showed partial loss. Surface electrostatics emphasised the significance of a positive patch on the binding surface of p16 that faces the CDK4 which was directly impacted due to mutations. Additionally, the partial binding mutants were found to have a lower stability compare to the Wildtype p16/CDK4 complex through the free energy landscape calculations. These findings provide useful insights into the molecular mechanisms by which p16 mutations influence CDK4 binding, potentially informing therapeutic strategies.