In this study we have calculated the acidity constant (pKa) of imidazole ring in Histidine-Hydrophobic amino acid dipeptides using the quantum chemistry and continuum solvation methods. Density functional theory (DFT) calculations with the large basis sets are used to determine the Gibbs free energy of deprotonate in the gas and liquid phases. Based on our results ΔGS values are located between −69.38 and−18.82 kcal mol−1 which are related to His+−Gly and His forms respectively. Aqueous-phase pKa of the dipeptides was obtained from the calculated gas-phase and solvation free energies via a thermodynamic cycle and the solvation model chemistry of Martin Karplus et al. Solvation effects are treated using a self-consistent reaction field (SCRF) formalism involving polarized continuum models (PCM). According to our calculations pKa values are between 5.50 and 8.19 that belong to His+−ILe and His+−Ala forms respectively. NBO analysis of dipeptides reveals that the electron delocalization in imidazole ring is the most effective factor in determination of acidity order at these compounds. Based on structural and atoms in molecules (AIM) analysis confirmed that the orientation of carbonyl group with respect to imidazole ring is an effective factor in imidazole ring stability.

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