Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method.

A new highly efficient interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field is employed to investigate the interaction mechanism of CDK2-ligand binding and the effect of the bridging water. Our result shows that the computed binding free energies for five CDK2-ligand complexes using the IE method have a significantly linear correlation with the experimentally measured values with a correlation coefficient of 0.98 in consideration of the bridging water under the PPC force field. And the correlation coefficient is found to be slightly weaker with a value of 0.95 using the traditional normal mode (Nmode) method for calculation of entropy change. Importantly, the rank of the predicted binding free energies is significantly consistent with the experimental rank based on the IE method calculated entropy change using the PPC force field. However, without including the bridging water under PPC simulation, the correlation coefficient is below 0.83. For comparison, the result obtained from the simulation using the nonpolarized AMBER force field gives a much weaker correlation with the correlation coefficients of 0.44 and 0.45 using the Nmode method and IE method, due to the lack of electrostatic polarization. Furthermore, hydrogen bond analysis indicates that the bridging water makes a significant contribution to mediating the hydrogen bond network of protein-ligand binding and stabilizing the complex structure. The current study demonstrates that the new IE method is superior to the standard Nmode method in computing the binding free energy. And our results also emphasize the importance of electronic polarization and bridging water in MD simulations and free energy calculations.