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

Abstract

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.

Automated exploration of the low-energy chemical space with fast quantum chemical methods

“…This is qualitatively consistent with results for other DFT or QM methods observed in Ref. 577. Errors at the GFN2-xTB/ALPB level were larger on average and in particular for the R-C-H, R2-NH, R-NH 2 , and R/Ph-COOH subsets.…”

“…For this purpose CFER fits were performed on the TR224 set introduced by Thapa and Raghavachari. 577 The TR224 set contains more reference Interesting observations can be made from the presented data. Despite the assumption in the previous section, no universal or "default" CFER should be applied for all levels of theory.…”

“…The respective structures were either taken from the literature 45,543,557,560,577 as Cartesian coordinates directly or converted from SMILES codes using OpenBabel. 586 However, we note that, if desired, protonation sites and tautomers could easily be screened 33,220 and included within the same computational framework.…”

“…[564][565][566] One major source of error for computed pK a values is the description of solvation effects, which are commonly treated by implicit solvation models 252,543,553,560,[567][568][569][570][571] , explicit solvation 572,573 or a combination thereof. [574][575][576][577] Nonetheless, predictions of the pK a based purely on QM have been proven…”

Structural properties of the chelating agent 2,6-bis(1-(3-hydroxypropyl)-1,2,3-triazol-4-yl)pyridine: a combined XRD and DFT structural study

“…In particular, the relative free energy of all four conformers was re-evaluated in the presence of an implicit solvent, modelled as a continuum dielectric medium with an aptly-shaped cavity in which the solute is lodged. While handling of explicit solvent molecules is problematic [41][42][43][44][45] (e.g. added degrees of freedom, shallow intermolecular potential energy wells, multiplicity of spatial arrangements), implicit solvation models have been proven in numerous occasions to provide a reliable description of shortrange and long-range solute-solvent interactions.…”