An atomistic workflow for determining acid-base prototropic tautomer microstate populations

We present a new cheminformatics package, Protomer Enumerator & Automatic Calculator for Energies (PEACE), which lists the prototropic forms of a given acid or base, and predicts which of these microstates are likely to be present in solution. The workflow enumerates prototropic tautomers, and orchestrates inexpensive semi-empirical quantum chemical simulations to evaluate their single-point energies, solvation free energies, entropic contributions, and ultimately their solution-phase energies. The relative population of each tautomer is then calculated. PEACE includes automatic error checks, tautomer screening, and conformer generation to improve speed and accuracy. It can be run in several solvent systems and on charged solutes. Herein, we demonstrate the workflow's efficacy on numerous practical benchmarks including on druglike molecules. The workflow is freely available for use through the command line with minimal package dependencies.