A fast and simple method to calculate protonation states in proteins

A simple model for electrostatic interactions in proteins, based on a dista nce and position dependent screening of the electrostatic potential, is pre sented. It is applied in conjunction with a Monte Carlo algorithm to calcul ate pK(alpha) values of ionizable groups in proteins. The purpose is to fur nish a simple, fast, and sufficiently accurate model to be incorporated int o molecular dynamic simulations, This will allow for dynamic protonation ca lculations and for coupling between changes in structure and protonation st ate during the simulation. The best method of calculating protonation state s available today is based on solving the linearized Poisson-Boltzmann equa tion on a finite difference grid, However, this model consumes far too much computer time to be a practical alternative. Tests are reported for fixed structures on bacteriorhodopsin, lysozyme, myoglobin, and calbindin. The st udies include comparisons with Poisson-Boltzmann calculations with dielectr ic constants 4 and 20 inside the protein, a model with uniform dielectric c onstant 80 and distance-dependent dielectric models. The accuracy is compar able to that of Poisson-Boltzmann calculations with dielectric constant 20, and it is considerably better than that with epsilon = 4. The time to calc ulate the protonation at one pH value is at least 100 times less than that of a Poisson-Boltzmann calculation. Proteins 1999;36:474-483. (C) 1999 Wile y-Liss, Inc.