Calculations of enzymatic reactions: calculations of pKa, proton transfer reactions, and general acid catalysis reactions in enzymes.

A method that allows one to correlate available X-ray data with activation free energies of enzymatic reactions is presented. This method is based on the empirical valence bond approach which uses experimental information to evaluate the energies of the valence bond resonance forms involved in a reaction and then calculates the environment-dependent stabilizations of the ionic resonance forms in the enzyme and in solution and correlates them with the rate acceleration by the enzyme. The method is reliable since it is based on calibration of potential surfaces by solution experiments and on transfer of the calibrated surface to the enzyme active site, using only simple calculations of electrostatic interactions. The close relation between the method and the intuitive valence bond description of bond-breaking bond-making reactions provides a new insight into enzymatic reactions, describing them as crossing between covalent and ionic valence bond resonance forms. Such a description correlates the stabilization of the ionic resonance forms by the enzyme active site with the enzyme catalytic activity. The paper considers the energetics of several enzymatic processes, including ionization, of acidic groups in enzyme active sites, stability of ion pairs in enzymes and in solutions, proton transfer reactions, and general acid catalysis reactions. The calculations support the idea that enzymes can be viewed as "supersolvents" that stabilize (solvate) ionic transition states more effectively than do aqueous solutions.