The protonation of the solvent-exposed histidine ligands of the type-1 Cu sites in five proteins, Thiobacillus ferrooxidans rusticyanin, Pseudomonas aeruginosa azurin, fern plastocyanin, Alcaligenes faecalis pseudoazurin, and Paracoccus versutus amicyanin, were studied with quantum chemical methods and conductorlike polarizable continuum model (CPCM). Active site model molecules consisting of similar to 140 atoms were extracted from X-ray crystal structures and optimized with the homogeneous CPCM/B3LYP/6-31G* method with some atoms fixed. More accurate solvation effects were obtained using a recently developed heterogeneous CPCM method to describe the protein matrix and aqueous solvation of the model molecules. In the heterogeneous CPCM method different effective dielectric constants, 4, 10, and 78.39, were used for different portions of the surfaces encapsulating the active site model molecules. It is found that the two conformations of the protonated histidine, imidazolium unflipped and flipped, show similar energies in the model molecules of these five proteins. The calculated pK(a) values are comparable to experimental values. According to the calculations, the main determinants of the pK(a) values are local interactions contained in the model molecules and aqueous solvation effects, as well as protein matrix polarization.