Elucidating the conformational landscape of CDKs: implications for cell cycle regulation

Authors

• W Zhang
• Y Liu
• M Bergman H Jang
• R Nussinov

Abstract

Cyclin-dependent kinases (CDKs) play a pivotal role in cell cycle regulation, and their dysregulation is implicated in cancer. We aim to decode the differential activation dynamics and function of cyclin-D/CDK4 and cyclin-E/CDK2 complexes in the G1 phase and G1/S phase transition of the cell cycle, respectively. Through molecular dynamics simulations and protein-protein docking, we analyze the conformational dynamics of these complexes, with a focus on their differential activation kinetics - cyclin-E/CDK2's rapid activation versus cyclin-D/CDK4's slower activation. Moreover, we examine how different conformational ensembles of active CDK complexes relate to their catalytic efficiencies, aiming to uncover key structural characteristics that govern the slow cyclin-D/CDK4 and rapid cyclin-E/CDK2 catalytic activities. Additionally, the study explores the diversity of CDK-cyclin interacting pairs, evaluating whether other CDKs have multiple cyclin partners as observed in CDK2, and the implications of these interactions on cell cycle progression. By integrating computational approaches with available experimental data, this project aims to elucidate the activation mechanisms of CDK complexes, offering insights for drug design and understanding CDK-dysregulated cancers.

Scientific Focus Area: Computational Biology

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