Theoretical calculations of homoconjugation equilibrium constants in systems modeling acid–base interactions in side chains of biomolecules using the potential of mean force

The potentials of mean force (PMFs) were determined for systems forming cationic and anionic homocomplexes composed of acetic acid, phenol, isopropylamine, n‐butylamine, imidazole, and 4(5)‐methylimidazole, and their conjugated bases or acids, respectively, in three solvents with different polarity and hydrogen‐bonding propensity: acetonitrile (AN), dimethyl sulfoxide (DMSO), and water (H2O). For each pair and each solvent a series of umbrella‐sampling molecular dynamics simulations with the AMBER force field, explicit solvent, and counterions added to maintain a zero net charge of a system were carried out and the PMF was calculated by using the Weighted Histogram Analysis Method (WHAM). Subsequently, homoconjugation‐equilibrium constants were calculated by numerical integration of the respective PMF profiles. In all cases but imidazole stable homocomplexes were found to form in solution, which was manifested as the presence of contact minima corresponding to hydrogen‐bonded species in the PMF curves. The calculated homoconjugation constants were found to be greater for complexes with the OHO bridge (acetic acid and phenol) than with the NHN bridge and they were found to decrease with increasing polarity and hydrogen‐bonding propensity of the solvent (i.e., in the series AN > DMSO > H2O), both facts being in agreement with the available experimental data. It was also found that interactions with counterions are manifested as the broadening of the contact minimum or appearance of additional minima in the PMF profiles of the acetic acid‐acetate, phenol/phenolate system in acetonitrile, and the 4(5)‐methylimidazole/4(5)‐methylimidzole cation conjugated base system in dimethyl sulfoxide. © 2004 Wiley Periodicals, Inc. J Comput Chem 26: 235–242, 2005

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