Rationalization of the pK_a Values of Alcohols and Thiols Using Atomic Charge Descriptors and Its Application to the Prediction of Amino Acid pK_a’s

Abstract

In a first step toward the development of an efficient and accurate protocol to estimate amino acids' pKa's in proteins, we present in this work how to reproduce the pKa's of alcohol and thiol based residues (namely tyrosine, serine, and cysteine) in aqueous solution from the knowledge of the experimental pKa's of phenols, alcohols, and thiols. Our protocol is based on the linear relationship between computed atomic charges of the anionic form of the molecules (being either phenolates, alkoxides, or thiolates) and their respective experimental pKa values. It is tested with different environment approaches (gas phase or continuum solvent-based approaches), with five distinct atomic charge models (Mulliken, Löwdin, NPA, Merz-Kollman, and CHelpG), and with nine different DFT functionals combined with 16 different basis sets. Moreover, the capability of semiempirical methods (AM1, RM1, PM3, and PM6) to also predict pKa's of thiols, phenols, and alcohols is analyzed. From our benchmarks, the best combination to reproduce experimental pKa's is to compute NPA atomic charge using the CPCM model at the B3LYP/3-21G and M062X/6-311G levels for alcohols (R(2) = 0.995) and thiols (R(2) = 0.986), respectively. The applicability of the suggested protocol is tested with tyrosine and cysteine amino acids, and precise pKa predictions are obtained. The stability of the amino acid pKa's with respect to geometrical changes is also tested by MM-MD and DFT-MD calculations. Considering its strong accuracy and its high computational efficiency, these pKa prediction calculations using atomic charges indicate a promising method for predicting amino acids' pKa in a protein environment.

Density Functional Theory Calculation of pKa’s of Thiols in Aqueous Solution Using Explicit Water Molecules and the Polarizable Continuum Model

“…[3][4] Some interesting examples from material science include the use of substituted benzene thiols in molecular electronics, surface enhanced Raman spectroscopy and quantum electronic tunneling between plasmonic nanoparticle resonators. [5][6][7][8][9][10][11] Understanding of the properties and reactivities of thiols as a function of pH requires a reliable set of measured or calculated acid dissociation constants. The experimental determination of pK a 's is not always easy because of problems such as interference from other solutes in the complex substrate environment, difficulties in isolation of specific residues, complexity due to the solvent system, etc.…”

A Test of Various Partial Atomic Charge Models for Computations on Diheteroaryl Ketones and Thioketones

“…Partial atomic charges find application in the molecular modeling of several chemically relevant areas, such as explaining structural and reactivity differences between various molecules and their conformers [15][16][17], investigating charge transfers within a single molecule and between several molecules [18][19][20], and predicting pK a variations in series of molecules [21,22]. Since the definition of partial atomic charges is not strict, various models of partial atomic charges can, however, differ significantly in the reliability of their predictions.…”

Convergence of Atomic Charges with the Size of the Enzymatic Environment

“…The following examples illustrate their importance: molecular force fields use charges to model electrostatic interactions 1 ; the equilibrium constant of acid dissociation (pKa) can be related to the charge of the conjugate base [2][3][4][5][6] . Further, atomic charges can be used to provide more insight into the reactivity via the atom-condensed Fukui function (in a finite difference approximation), indicating the reactivity towards a nucleophilic or electrophilic attack of a soft reagent on a particular (protein) site 7 .…”