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-cancellation scheme that eliminates the systematic errors in different density functional methods to yield accurate pKa values for simple to complex molecular systems. Our protocol is efficient, applicable to large molecules, covers all the common functional groups present in bio-organic molecules, and should find widespread applications in diverse research areas including drug-protein binding, catalysis, and chemical synthesis.