Molecular mechanism concerning conformational changes of CDK2 mediated by binding of inhibitors using molecular dynamics simulations and principal component analysis

Cyclin-dependent kinase 2 (CDK2) has been regarded as a promising drug target for anti-tumour agents. In this study, molecular dynamics (MD) simulations and principal component (PC) analysis were used to explore binding mechanism of three inhibitors 1PU, CDK, 50Z to CDK2 and influences of their bindings on conformational changes of CDK2. The results show that bindings of inhibitors yield obvious impacts on internal dynamics, movement patterns and conformational changes of CDK2. In addition, molecular mechanics generalized Born surface area (MM-GBSA) was applied to calculate binding free energies between three inhibitors and CDK2 and evaluate their binding ability to CDK2. The results show that CDK has the strongest binding to CDK2 among the current three inhibitors. Residue-based free energy decomposition method was further utilized to decode the contributions of a single residue to binding of inhibitors, and it was found that three inhibitors not only produce hydrogen bonding interactions and hydrophobic interactions with key residues of CDK2, which promotes binding of three inhibitors to CDK2, but also share similar binding modes. This work is expected to be helpful for design of efficient drugs targeting CDK2.