Accurate pKa Evaluations for Complex Bio-Organic Molecules in Aqueous Media

Despite the numerous computational efforts on estimating acid dissociation constant (pKa’s), an accurate estimation of pKa’s of bio-organic molecules in the aqueous medium is still a challenge. The major difficulty lies in the accurate description of the aqueous environment and the cost and accuracy of quantum mechanical (QM) methods. Herein, we report a well-defined quantum chemical protocol for accurately calculating pKa’s of a wide range of bio-organic molecules in aqueous media. The performance of our method has been assessed using test sets containing molecules with a range of sizes and a variety of functional groups, including alcohols, phenols, amines, and carboxylic acids, and obtained an impressive mean absolute accuracy of 0.5 pKa units. For the smaller molecules, we use a high-level QM method (CBS-QB3) and a calibrated explicit–implicit solvation model that yields accurate pKa values for a range of functional groups. For the larger molecules, we combine this approach with an efficient error-can...