Explicit solvent models in protein pKa calculations

Abstract

Continuum methods for calculation of protein electrostatics treat buried and ordered water molecules by one of two approximations; either the dielectric constant of regions containing ordered water molecules is equal to the bulk solvent dielectric constant, or it is equal to the protein dielectric constant though no fixed atoms are used to represent water molecules. A method for calculating the titration behavior of individual residues in proteins has been tested on models of hen egg white lysozyme containing various numbers of explicit water molecules. Water molecules were included based on hydrogen bonding, solvent accessibility, and/or proximity to titrating groups in the protein. Inclusion of water molecules significantly alters the calculated titration behavior of individual titrating sites, shifting calculated pKa values by up to 0.5 pH unit. Our results suggest that approximately one water molecule within hydrogen-bonding distance of each charged group should be included in protein electrostatics calculations.

Are Acidic and Basic Groups in Buried Proteins Predicted to be Ionized?

“…The results with explicit and continuum water have been found to be comparable in many 19,78,83 but not all cases. 66,109,110 These proteins contain numerous non-amino acid groups co-crystallized with the protein. Hemes and their propionic acids are treated as described in our earlier studies.…”

Is the prediction of pKavalues by constant‐pH molecular dynamics being hindered by inherited problems?

“…Although we started this study using two of the Staphylococcal nuclease mutants from Garcia‐Moreno's Lab, serious issues were found involving the parametrization of neutral Arg and Lys groups, which are currently being investigated in detail. Therefore, we decided to use hen egg white lysozyme (HEWL), which has become, over the years, a standard test system for p K a prediction methodologies,7, 14–17, 22, 24, 30–50 because of the availability of accurate experimental data, and because it has a number of sites with p K a values that differ markedly from their reference values, mainly in the acidic range.…”

Modeling of protein conformational fluctuations in pKa predictions

“…The pK a values of the titrating groups of many proteins have been predicted by a continuum model, in which the protein and the solvent are represented by low and high dielectric media, respectively (Warshel et al, 1984;Wendoloski & Matthew, 1989;Bashford & Karplus, 1990;Beroza et al, 1991Beroza et al, , 1995Langsetmo et al, 1991;Bashford & Gerwert, 1992;Bashford et al, 1993;Oberoi & Allewell, 1993;Antosiewicz et al, 1994Antosiewicz et al, , 1996McDonald et al, 1995;You & Bashford, 1995;Gibas & Subramaniam, 1996). A well-documented result is that the predicted pK a values can differ by several pK units if different conformations of the protein are used (Wendoloski & Matthew, 1989;Langsetmo et al, 1991;Bashford & Gerwert, 1992;Bashford et al, 1993;Oberoi & Allewell, 1993;You & Bashford, 1995;Antosiewicz et al, 1996).…”