Structural Plasticity Drives CDK1/CDK2 Isoform Selectivity: Atomistic Insights from Molecular Dynamics

Abstract

CDK1 and CDK2 are structurally near-identical kinases whose ATP-binding pockets share a global backbone RMSD of approximately 0.72 Å, yet certain inhibitors display up to 170-fold selectivity for CDK2 over CDK1. Crystal structures alone cannot explain this divergence. Here, we report 100 ns all-atom molecular dynamics simulations of five CDK–inhibitor complexes involving three clinical-grade inhibitors, Dinaciclib, AZD5438, and CGP74514A, benchmarked against experimental isothermal titration calorimetry (ITC) data. Trajectory analysis reveals that isoform selectivity is encoded in local pocket dynamics rather than global structural differences.