Prediction and rationalization of protein pK _a values using QM and QM/MM methods

We describe the development and application of a computational method for the prediction and rationalization of pK _a values of ionizable residues in proteins, based on ab initio quantum mechanics (QM) and the effective fragment potential (EFPs) method (a hybrid QM/MM method). The theoretical developments include (1) a covalent boundary method based on frozen localized orbitals, (2) divide-and-conquer methods for the ab initio computation of protein EFPs consisting of multipoles up to octupoles and dipole polarizability tensors, (3) a method for computing vibrational free energies for a localized molecular region, and (4) solutions of the polarized continuum model of bulk solvation equations for protein-sized systems. The QM-based pK _a prediction method is one of the most accurate methods currently available and can be used in cases where other pK _a prediction methods fail. Preliminary analysis of the computed results indicate that many pK _a values (1) are primarily determined by hydrogen bonds rather than long-range charge-charge interactions and (2) are relatively insensitive to large-scale dynamical fluctuations of the protein structure.