The conformational preferences of the Cys dipeptides with thiol and thiolate groups (Ac-Cys-NHMe and Ac-Cys (-)-NHMe, respectively) and the apparent (i.e., macroscopic) p K a value of the Cys dipeptide have been studied at the hybrid density functional B3LYP/6-311++G(d,p)//B3LYP/6-31+G(d) level with the conductor-like polarizable continuum model in the gas phase and in water. The hydrogen bonds and/or favorable interactions between the backbone and the thiol group of the side chain resulted in the different conformational preferences of the Cys and Cys (-) dipeptides from those of the Ala dipeptide in the gas phase and in water, although the preferred conformations of the Cys dipeptide are in part similar to those of the Ala dipeptide. In particular, the interactions between the thiolate group and the backbone amide groups appear to play a role in stabilizing the alpha- or 3 10-helical conformations for the Cys (-) dipeptide in the gas phase and in water. The p K a value of the Cys residue is estimated to be 8.58 at 25 degrees C using the statistically weighted free energies of all feasible conformations for the Cys and Cys (-) dipeptides in the gas phase and solvation free energies, which is consistent with the observed values of 8.3 and 8.22 +/- 0.16.