Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

Abstract

The rational development of specific inhibitors for the ∼500 protein kinases encoded in the human genome is impeded by 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 like 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.2

Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors

“…It is obvious that the best scoring function is able to explain only about 70% of the data variability and that the available scoring functions are not capable of describing all the physics behind the inhibitor binding to CDK2. Many authors have analysed the nature of CDK2-inhibitor binding using various methods and concluded that the dispersion interactions (part of van der Waals interactions) is important for inhibitor binding [17,18,27,68] and may outweigh electrostatics [23]. Evidently, however, not only the dispersion but also the other terms should be properly covered.…”

Applications of large-scale density functional theory in biology

“…Quantum mechanical / Poisson Boltzmann Approaches. One of the earliest applications in a biological context of the local orbital methods described in Section 1.2.3 was performed by Heady et al to compute the free energy of binding of five inhibitors to the cyclin-dependent kinase CDK2 [267]. The motivation for studying the target CDK2 is that it is over-expressed in cancer cells and may contribute to their unregulated growth [271].…”

Electrostatic embedding in large-scale first principles quantum mechanical calculations on biomolecules

“…24 Even though it is a new code, it is already being used in an increasing number of studies of nanostructures 25 and biomolecular systems. [26][27][28] An example of the linear-scaling behaviour of the code is provided in Figure 1 where the time to perform single-point energy calculations on protein fragments of increasing size is plotted as a function of the number of atoms. In these calculations a value of r K = 10.6 Å was used.…”