Abstract
The protonation/deprotonation reaction is one of the most fundamental processes in solutions and biological systems. Compounds with dissociative functional groups change their charge states by protonation/deprotonation. This change not only significantly alters the physical properties of a compound itself, but also has a profound effect on the surrounding molecules. In this paper, we review our recent developments of the methods for predicting the Ka, the equilibrium constant for protonation reactions or acid dissociation reactions. The pKa, which is a logarithm of Ka, is proportional to the reaction Gibbs energy of the protonation reaction, and the reaction free energy can be determined by electronic structure calculations with solvation models. The charge of the compound changes before and after protonation; therefore, the solvent effect plays an important role in determining the reaction Gibbs energy. Here, we review two solvation models: the continuum model, and the integral equation theory of molecular liquids. Furthermore, the reaction Gibbs energy calculations for the protonation reactions require special attention to the handling of dissociated protons. An efficient method for handling the free energy of dissociated protons will also be reviewed.
Highlights
The protonation and deprotonation reactions of dissociative functional groups in solvated compounds often play essential roles in chemical and biological processes, such as solvation, protein–ligand binding, and the higher-order structure formation of proteins
We review our recent developments of the computational methods for predicting pKa values, which are based on quantum chemical electronic structure methods combined with solvation models
Sprik and coworkers proposed a method for obtaining the free-energy profile due to acid dissociation from density functional theory (DFT)-based ab initio molecular dynamics (AIMD) simulations and successfully obtained the pKa values of many compounds, including amino acids in aqueous solution [4]
Summary
The protonation and deprotonation reactions of dissociative functional groups in solvated compounds often play essential roles in chemical and biological processes, such as solvation, protein–ligand binding, and the higher-order structure formation of proteins. We review two different solvation models: the polarizable continuum model (PCM) and the reference interaction site model (RISM) theories Quantum chemical calculations, such as density functional theory (DFT), can often be used to avoid the computational parameter dependence. Sprik and coworkers proposed a method for obtaining the free-energy profile due to acid dissociation from DFT-based ab initio molecular dynamics (AIMD) simulations and successfully obtained the pKa values of many compounds, including amino acids in aqueous solution [4] This method is highly accurate for pKa prediction, long computation times are required to obtain the solvation free-energy difference, indicating that it is only applicable to small molecules.
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