Revisiting the Carboxylic Acid Dimers in Aqueous Solution:  Interplay of Hydrogen Bonding, Hydrophobic Interactions, and Entropy

Abstract

Carboxylic acid dimers are useful model systems for understanding the interplay of hydrogen bonding, hydrophobic effects, and entropy in self-association and assembly. Through extensive sampling with a classical force field and careful free energy analysis, it is demonstrated that both hydrogen bonding and hydrophobic interactions are indeed important for dimerization of carboxylic acids (except formic acid). The dimers are only weakly ordered, and the degree of ordering increases with stronger hydrophobic interactions between longer alkyl chains. Comparison of calculated and experimental dimerization constants reveals a systematic tendency for excessive self-aggregation in current classical force fields. Qualitative and quantitative information on the thermodynamics of hydrogen bonding and hydrophobic interactions derived from these simulations is in excellent agreement with existing results from experiment and theory. These results provide a verification from first principles of previous estimations based on two statistical mechanical hydrophobic theories. We also revisit and clarify the fundamental statistical thermodynamics formalism for calculating absolute binding constants, external entropy, and solvation entropy changes upon association from detailed free energy simulations. This analysis is believed to be useful for a wide range of applications including computational studies of protein-ligand and protein-protein binding.

Chemical Rescue of Enzymes: Proton Transfer in Mutants of Human Carbonic Anhydrase II

“…The method for calculating the pK a is discussed in ref 53 and incorporates the contributions due to the standard state correction. 59 The $V_{ii}^0$ term was then systematically changed and the PMF and pK a recalculated until the pK a of the 4MI ionizable residue matched the experimentally determined value. The resulting $V_{ii}^0$ term for 4MI is −105.1 kcal/mol as compared to histidine’s $V_{ii}^0$ value of −101.4 kcal/mol.…”

Effects of arginine on multimodal anion exchange chromatography

“…The estimation of the binding free energy provides insights into conformational stabilities of the interaction as mentioned below. Notably, the free energy obtained from the umbrella sampling simulations generally ignores the contribution of entropy, which is associated with the radial distribution (i.e., the contribution from an apparent centrifugal force) [38]. Thus, the entropic term r RT ln 2 − was excluded in this study.…”

Prediction of aqueous solubilities of solid carboxylic acids with COSMO-RS

“…For instance, carboxylic acids are known to form dimers in the gas phase and in non-polar solvents, whereas in aqueous solution, at low concentrations the intermolecular association of carboxylic acid molecules is replaced by hydrogen bonding to water [27]. Dimer formation in aqueous solution is subject of ongoing discussion [28]. At concentrations sufficiently low, even very weak electrolytes (pK a ∼ 10) dissociate to a certain extent.…”