  The rational development of specific inhibitors for the ~500 protein kinases
encoded in the human genome is impeded by a poor understanding of the
structural basis for the activity and selectivity of small molecules that
compete for ATP binding. Combining classical dynamic simulations with a novel
ab initio computational approach linear-scalable to molecular interactions
involving thousands of atoms, we have investigated the binding of five distinct
inhibitors to the cyclin-dependent kinase CDK2. We report here that
polarization and dynamic hydrogen bonding effects, so far undetected by
crystallography, affect both their activity and selectivity. The effects arise
from the specific solvation patterns of water molecules in the ATP binding
pocket or the intermittent formation of hydrogen bonds during the dynamics of
CDK/inhibitor interactions and explain the unexpectedly high potency of certain
inhibitors such as
3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The
Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary
hydrogen bonds with the three most potent inhibitors. This residue is replaced
in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds,
explaining the relative selectivity of the inhibitors for CDK2. Our results
provide a generally applicable computational method for the analysis of
biomolecular structures and reveal hitherto unrecognized features of the
interaction between protein kinases and their inhibitors
