ABSOLUTE PKA CALCULATIONS WITH CONTINUUM DIELECTRIC METHODS

Solvation free energies and pK(a) values of models for ionizable side chains of amino acids are calculated by using continuum dielectric methods; integral equation techniques are also investigated. The dependence of the solvation free energies on the parameters (charges and van der Waals interactions used to describe the model compounds) is explored by comparing different sets that are being used in protein and liquid simulations. The solvation free energies calculated with both continuum and integral equation methods and various parameter sets agree qualitatively with experiment but are not accurate enough to yield absolute pK(a) values. To obtain the experimental solvation free energies and pK(a) values of the model compounds with the continuum dielectric method, an adjusted parameter set is introduced; only very small changes from the standard parameter values are required. The set of calibrated parameters is tested on some bifunctional compounds and yields pK(a) changes in reasonable agreement with experiment. However, the pK(a) changes are very sensitive to the solution conformation. This may result in large pK(a) errors if conformational changes (e.g., between the ionized and neutral species) are not taken into account.