Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations

CDK2 can be used as an attractive target for development of efficient inhibitors curing multiple disease relating with CDK2. In this work, molecular dynamics (MD) simulations and binding free energy calculations were coupled to probe conformational changes of CDK2 due to inhibitor associations and binding mechanisms of inhibitors PM1, FMD and X64 to CDK2. The results suggest that the binding strength of FMD and X64 to CDK2 is stronger than that of PM1. Principal component (PC) analysis and cross-correlation map calculations based on the equilibrated MD trajectories demonstrate that the structural difference in inhibitors exerts important impact on motion modes and dynamics behavior of CDK2. Residue-based free energy decomposition method was adopted to estimate the inhibitor-residue spectrum. The results not only efficiently identify the hot interaction spot of inhibitors with CDK2 but also show that the hydrophobic rings R1, R2 and R3 as well as polar groups of three inhibitors play key roles in favorably binding of inhibitors to CDK2. This work is expected to contribute energetic basis and dynamics information to development of promising inhibitors toward CDK2.