The ionization state of titratable amino acids strongly affects proteins structure and functioning in a large number of biological processes. It is therefore essential to be able to characterize the pKa of ionizable groups inside proteins and to understand its microscopic determinants in order to gain insights into many functional properties of proteins. A big effort has been devoted to the development of theoretical approaches for the prediction of deprotonation free energies, yet the accurate theoretical/computational calculation of pKa values is recognized as a current challenge. A methodology based on a hybrid quantum/classical approach is here proposed for the computation of deprotonation free energies. The method is applied to calculate the pKa of formic acid, methylammonium, and methanethiol, providing results in good agreement with the corresponding experimental estimates. The pKa is also calculated for aspartic acid and lysine as single residues in solution and for three aspartic/glutamic acids inside a well-characterized protein: hen egg white lysozyme. While for small molecules the method is able to deal with multiple protonation states of all titratable groups, this becomes computationally very expensive for proteins. The calculated pKa values for the single amino acids (except for the zwitterionic aspartic acid) and inside the protein display a systematic shift with respect to the experimental values that suggests that the fine balance between hydrophobic and polar interactions might be not accurately reproduced by the usual classical force-fields, thus affecting the computation of deprotonation free energies. The calculated pKa shifts inside the protein are in good agreement with the corresponding experimental ones (within 1 pKa unit), well reproducing the pKa changes due to the protein environment even in the case of large pKa shifts.