Improving pKa calculations with consideration of hydration entropy.

Continuum dielectric modelling of electrostatics interactions in macromolecules provides a valuable tool in the study of structure-function relationships, but falls short of providing consistently accurate calculated pKas. It is suggested that the model can be significantly improved with the inclusion of a term that estimates the entropy associated with first hydration shell solvent ordering, with reference to computed results for cysteines in DsbA and thioredoxin, and aspartic and glutamic acids in a number of proteins. The modification is based on the geometry of charge burial and an hydration number, which is adjustable (by fit to experiment), and is uniform within each class of ionizable group studied. The potential for further development is clear within this framework, since experiment and simulation can furnish non-adjustable, ionizable group-specific, hydration numbers.