Computer Prediction of p K a Values in Small Molecules and Proteins

Abstract

Accurately determining the acid dissociation constants (K _a or their logarithmic form, pK _a) of small molecules and large biomolecules has proven to be pivotal for the study different biological processes and developing new drugs. This Viewpoint summarizes some of the most common methodologies and recent advances described for pK _a prediction using computational techniques when experimental values are not easily accessible such as in proteins and/or for the screening of large libraries of new compounds.

Figure 1

Protonation equilibria of cetirizine. Microequilibria are shown above, and macrostates (i.e., proton count) are shown below. Acid dissociation micro- and macroconstants (measured experimentally) are shown in blue and green, respectively. Dashed rectangle highlights the major species at physiological pH.

Figure 2

Thermodynamic cycle for the proton exchange between a monoprotic acid (HA) and the solvent (H₂O) used to compute the Gibbs free energy of dissociation in solution (ΔG_aq). Labels (g) and (aq) denote gas and aqueous phases, respectively. ΔG_sol are (de)solvation Gibbs free energies.