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The rational development of specific inhibitors for the ~500 protein kinasesencoded in the human genome is impeded by a poor understanding of thestructural basis for the activity and selectivity of small molecules thatcompete for ATP binding. Combining classical dynamic simulations with a novelab initio computational approach linear-scalable to molecular interactionsinvolving thousands of atoms, we have investigated the binding of five distinctinhibitors to the cyclin-dependent kinase CDK2. We report here thatpolarization and dynamic hydrogen bonding effects, so far undetected bycrystallography, affect both their activity and selectivity. The effects arisefrom the specific solvation patterns of water molecules in the ATP bindingpocket or the intermittent formation of hydrogen bonds during the dynamics ofCDK/inhibitor interactions and explain the unexpectedly high potency of certaininhibitors such as3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). TheLys89 residue in the ATP-binding pocket of CDK2 is observed to form temporaryhydrogen bonds with the three most potent inhibitors. This residue is replacedin CDK4 by Thr89, whose shorter side-chain cannot form similar bonds,explaining the relative selectivity of the inhibitors for CDK2. Our resultsprovide a generally applicable computational method for the analysis ofbiomolecular structures and reveal hitherto unrecognized features of theinteraction between protein kinases and their inhibitors

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations