Modeling Polarization in Proteins and Protein–ligand Complexes: Methods and Preliminary Results

Abstract

This chapter discusses methods for modeling electronic polarization in proteins and protein-ligand complexes. Two different approaches are considered: explicit incorporation of polarization into a molecular mechanics force field and the use of mixed quantum mechanics/molecular mechanics methods to model polarization in a restricted region of the protein or protein-ligand complex. A brief description is provided of the computational methodology and parameterization protocols and then results from two preliminary studies are presented. The first study employs quantum mechanics/molecular mechanics (QM/MM) methods to improve the accuracy of protein-ligand docking; here, incorporation of polarization is shown to dramatically improve the robustness of the accuracy of structural prediction of the protein-ligand docking by enabling qualitative improvement in the selection of the correct hydrogen bonding patterns of the docked ligand. The second study discusses a 2-ns simulation of bovine pancreatic trypsin inhibitor (BPTI) in water using a variety of fixed charge and polarizable models for both the protein and the solvent, analyzing observed root mean square deviations (RMSD), intraprotein hydrogen bonding, and water structure and dynamics. All of these efforts are in a relatively early stage of development, the results are encouraging in that stable methods have been developed, and significant effects of polarization are seen and (in the case of the QM/MM-based docking) improvements have been validated as compared to experiment. With regard to accuracy and robustness of full simulations, a great deal more work needs to be done to quantitate and improve the present models.