Optimizing the hydrogen‐bond network in Poisson–Boltzmann equation‐based pKa calculations

Abstract

PK_a calculation methods that are based on finite difference solutions to the Poisson–Boltzmann equation (FDPB) require that energy calculations be performed for a large number of different protonation states of the protein. Normally, the differences between these protonation states are modeled by changing the charges on a few atoms, sometimes the differences are modeled by adding or removing hydrogens, and in a few cases the positions of these hydrogens are optimized locally. We present an FDPB-based pK_a calculation method in which the hydrogen-bond network is globally optimized for every single protonation state used. This global optimization gives a significant improvement in the accuracy of calculated pK_a values, especially for buried residues. It is also shown that large errors in calculated pK_a values are often due to structural artifacts induced by crystal packing. Optimization of the force fields and parameters used in pK_a calculations should therefore be performed with X-ray structures that are corrected for crystal artifacts. Proteins 2001;43:403–412.