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

Despite the numerous computational efforts on estimating acid dissociation constant (pK_a's), an accurate estimation of pK_a'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 pK_a'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 pK_a units. For the smaller molecules, we use a high-level QM method (CBS-QB3) and a calibrated explicit-implicit solvation model that yields accurate pK_a 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 pK_a 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.