3.1 Introduction

Assessment of ligand pKas can be broken into two phases. The first phase is enumeration of the protonation states of interest, and the second phase is assigning a pKa value to each of these states. An intermediate phase of assigning microscopic pKas to each of the atomic-deprotonations may also be considered.

It is common in the course of modeling small-molecules to explore the conformational ensemble of the small molecule. Often structures as high as 5-8 kcal above the aqueous ground-state can be important to biological processes. It is appropriate to also enumerate a protonation-state ensemble of the small molecule.

Similar to tautomers, OpenEye has a solution for enumerating reasonable protonation states, but not for assessing the energetics of the state (e.g. assigning a pKa value). OpenEye's solution for pKa enumeration seeks to enumerate all of the pKa states that fall roughly in the range of 2-14 in aqueous solvent. This range of pKa values generates an ensemble that includes the ground-state plus all charge states within 8 kcals $\Delta$ G. This value was chosen to correspond to the similar range that is often used for generating conformational ensembles of small molecules.

				QuacPac Quality Atomic Charges, Proton Assignment and Canonicalization