| Abstract
| - Poisson−Boltzmann (PB) models are a fast and common tool for studying electrostatic processes in proteins,particularly their ionization equilibrium (protonation and/or reduction), often yielding quite good results whencompared with more detailed models. Yet, they are conceptually very simple and necessarily approximate,their empirical character being most evident when it comes to the choice of the dielectric constant assignedto the protein region. The present study analyzes several factors affecting the ability of PB-based methods tomodel protein ionization equilibrium. We give particular attention to a suggestion made by Warshel andco-workers (e.g., Sham et al. J. Phys. Chem. B1997, 101, 4458) of using different protein dielectric constantsfor computing the individual (site) and the pairwise (site−site) terms of the ionization free energies. Ourprediction of pKa values for several proteins indicates that no advantage is obtained by such a procedure,even for sites that are buried and/or display large pKa shifts relative to the solution values. In particular, thepresent methodology gives the best predictions using a dielectric constant around 20, for shifted/buried andnonshifted/exposed sites alike. The similarities and differences between the PB model and Warshel's PDLD/Smodel are discussed, as well as the reasons behind their apparently discrepant results. The present PB modelis shown to predict also good reduction potentials in redox proteins.
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