Cyclin-E/A/CDK1/2 Kinetic Landscapes Drive Cell Cycle Phase-Specific Progression and Guide Cyclin-E Degradation Strategy.

The cell cycle relies on sequential activation of cyclin-dependent kinases (CDKs) by phase-specific cyclins. Previously, we proposed that their conformations and activation speed are tuned to the needs of their respective phases. We demonstrated this principle by using molecular dynamics simulations to evaluate the slower activation and catalytic kinetics of Cyclin-D/CDK4 during the long G₁ phase compared to the rapid activation of Cyclin-E/CDK2 in the brief G₁/S transition, and the higher intrinsic activity of Cyclin-D/CDK6 required for rapid hematopoietic cell proliferation. Here, we ask whether this principle also holds for subsequent cell cycle phases. We explore how the dynamic behavior of structurally similar Cyclin-E/CDK2, Cyclin-A/CDK2, and Cyclin-A/CDK1 controls their distinct tasks, and how the cell ensures that Cyclin-A/CDK2 and Cyclin-A/CDK1, which share the same allosteric effector Cyclin-A, avoid redundantly triggering S and M-phase events out of order. Through molecular dynamics simulations, we find that their functional differences relate to their distinct conformational energy landscapes and kinetic profiles. Unlike the plastic interface of CDK1 complexes, the Cyclin-E/CDK2 complex, governing the G₁/S transition, is conformationally constrained by a stable interface and is less dependent on its catalytic outputs. In contrast, the high catalytic efficiency of Cyclin-A/CDK2 can support rapid phosphorylation of S phase replication factors, thereby preventing DNA rereplication through preorganization of the CDK2 DFG-motif. We translate our results to the clinic by proposing an innovative allosteric degrader strategy for selective Cyclin-E degradation. We further validate our design workflow by reproducing the ternary complex of a known CDK2 degrader, and applying this approach to model an allosteric degrader thereby establishing the structural parameters required to target this specific Cyclin-E/CDK2-cereblon conformational state.