Defined-sector explicit solvent in the continuum model approach for computational prediction of pK_a

Abstract

Accurate prediction of the acidity dissociation constant (K _a) is a challenge for the theory of proton-transfer reactions, making first-principles prediction of pK _a within 0.5 pK units of experimental values a benchmark of broad interest. In the present contribution, the defined-sector explicit solvent in continuum cluster model, which considers the structure-to-chemical affinity relationship of the carboxyl functional group, is presented. The model demonstrates predictable solvent networks based on established ‘preferred’ conformations found in a training set. Predictability within 1 kcal mol^–1 accuracy is shown for a full set of carboxylic acid systems with varying functionality.

Keywords:

• pK _a
• directed interactions
• nonelectrostatic effects
• continuum cluster
• explicit solvent

Acknowledgements

We acknowledge the University of Zürich and the Swiss National Science Foundation for support of this research. We are grateful to Prof. Jay S. Siegel and Prof. Don D. Truhlar for helpful discussions.