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 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 DGS values are located between
69.38 and
18.82 kcal mol
1 which are related to His þ –Gly and His forms, respectively. pKa of the dipeptides in the aqueous phase was obtained from the calculated gas-phase and solvation free energies through a thermodynamic cycle and the solvation model chemistry of Martin Karplus et al. Solvation effects are treated using a selfconsistent reaction field formalism involving polarized continuum models. According to our calculations pKa values are between 5.50 and 8.19 that are belong to His þ –ILe and His þ –Ala forms, respectively. Natural bond orbital analysis of dipeptides reveals that the electron delocalization in imidazole ring is the most effective factor in determination of acidity order for these compounds. Structural 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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