Arun D, Rath Soumya Lipsa
Department of Biotechnology, National Institute of Technology Warangal, Hanamkonda, Telangana, India.
Mol Divers. 2025 Jan 17. doi: 10.1007/s11030-024-11089-z.
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.
细胞周期蛋白依赖性激酶（CDKs）在细胞周期进程中发挥着至关重要的作用。CDK活性通过磷酸化作用以及诸如p16等CDK抑制剂的抑制作用来控制。p16中的突变可导致诸如癌症等疾病。本研究利用建模、分子动力学模拟和对接研究，考察了一系列p16突变体及其与CDK4的分子相互作用。尽管p16因突变而未发生显著的结构变化，但发现其结合亲和力受到影响，这与保守性尺度相关。模拟结果显示，特定突变，如G23D、P114S和A60V导致与CDK4的结合丧失，而其他突变，如R24Q和G67R则表现出部分丧失。表面静电学强调了p16面向CDK4的结合表面上一个正性区域的重要性，该区域因突变而受到直接影响。此外，通过自由能景观计算发现，与野生型p16/CDK4复合物相比，部分结合突变体具有较低的稳定性。这些发现为p16突变影响CDK4结合的分子机制提供了有用的见解，可能为治疗策略提供依据。
