Generation of tautomers using micro-pKa's

Solutions of organic molecules containing one or more heterocycles with a number of conjugated bonds may exist as a mixture of tautomers, but typically only a very few will be significantly populated even though the potential number grows combinatorially with the number of protonation and deprotonation sites. Generating the most stable tautomers a priori from a given input structure is therefore an important and challenging task and numerous algorithms have been proposed in the literature. This work describes a novel approach for tautomer prediction, which involves a combined use of molecular mechanics, semi-empirical quantum chemistry, and density functional theory. The key idea in our method is to identify the protonation and deprotonation sites using estimated micro-pKa's for every atom in the molecule, as well its nearest protonated and deprotonated forms. To generate tautomers in a systematic way with minimal bias, we then consider the full set of tautomers that arise from the combinatorial distribut...