# pkatyper - Ligand pKa¶

## 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/mol above the aqueous ground-state can be important to biological processes. It is also appropriate to 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 pH 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/mol $$\Delta G$$. This value was chosen to correspond to the similar range that is often used for generating conformational ensembles of small molecules.

## Theory¶

pkatyper enumerates charge states based on primary, secondary and tertiary atom types of each atom in a molecule. The primary atom type is based on the atom’s group and its valence. The primary atom-type defines the atom’s basic propensity to support a formal charge. The secondary atom-type is defined by the atom-type of the neighbors for each atom. These secondary atom-types, such as aromaticity, alpha-beta unsaturation, or electronegative-groups, modulate each atom’s basic propensity to support formal charges. The tertiary atom-types assess the effects of nearby formal charges on a given atom’s formal charge. The combination of the primary, secondary and tertiary atom-types determine which formal charge states are allowed for each atom in a molecule. The primary and secondary atom-types are determined once, while the tertiary atom-types are determined as part of the enumeration process.

pkatyper is a rudimentary approach to pKa prediction. While pkatyper is not suited for prediction of absolute pKas, it is quite amenable to enumeration of all reasonable charge states of a very wide variety of small-molecule chemistries.

pkatyper is not a conformer generation program and will not create coordinates for molecules that are read in without coordinates. When used on molecules with three-dimensional coordinates, pkatyper attempts to place new hydrogens in a reasonable manner. However, pkatyper does not modify the heavy-atom coordinates of the molecule. In cases where the change in protonation-state dictates a change in conformation, one will need to use a conformer-generation tool (such as OMEGA) to generate reasonable conformations for the output from pkatyper. We recommend that in preparation of small-molecules for study, charge-state and tautomer enumeration be performed before conformer generation.

In the future, OpenEye will release a product which assigns a pKa value to each of the enumerated states.