Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ

CopZ is a copper chaperone from Bacillus subtilis. It is an important part of Cu(I) trafficking. We have calculated pKa values for the CXXC motif of this protein, which is responsible for the Cu(I) binding, and the Cu(I) binding constants. Polarizable and fixed‐charges formalisms were used, and solvation parameters for the both models have been refitted. We had to partially redevelop parameters for the protonated and deprotonated cysteine residues. We have discovered that the polarizable force field (PFF) is qualitatively superior and allows a uniformly better level of energetic results. The PFF pKa values for cysteine are within about 0.8–2.8 pH units of the experimental data, while the fixed‐charges OPLS formalism yields errors of up to tens of units. The PFF magnitude of the copper binding energy is about 10 kcal/mol or 50% higher than the experimental value, while the using the refitted OPLS parameters leads to an overall positive binding energy, thus predicting no thermodynamically stable complex. At the same time, the agreement of the polarizable S···Cu(I) distances with the experimental results is within 0.08 Å range, and the nonpolarizable calculations lead to an error of about 0.4 Å. Moreover, the accuracy of the PFF has been achieved without any explicit fitting to either pKa or CopZ···Cu(I) binding energies. We believe that this makes our polarizable technique a choice method in reproducing protein—copper binding and further supports the notion that explicit treatment of electrostatic polarization is crucial in many biologically relevant studies, especially ion binding and transport. © 2012 Wiley Periodicals, Inc.