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VOL. 10, ISSUE 2 (2026)
Structural plasticity drives CDK1/CDK2 isoform selectivity: Atomistic insights from molecular dynamics
Authors
Ganga Grazielia Chrisna, Chen Qu
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. CDK2 undergoes productive induced-fit
rearrangements, establishing dense, persistent hydrogen-bonding networks and a
tighter hydrophobic enclosure of the ligand. CDK1 is conformationally rigid,
prevents ordered water-mediated bridging, and permits repeated solvent exposure
of the bound inhibitor. Per-residue energy decomposition and contact map
analysis identify specific hinge-region and PSTAIRE-helix residues as the
primary determinants of selectivity.
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Pages:83-88
How to cite this article:
Ganga Grazielia Chrisna, Chen Qu "Structural plasticity drives CDK1/CDK2 isoform selectivity: Atomistic insights from molecular dynamics". International Journal of Chemical Science, Vol 10, Issue 2, 2026, Pages 83-88
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