Here, we consider a cysteine residue in the protein and a capped model peptide (i.e., ACE-Ala-Cys-Ala-NH 2 ) in both vacuum and water. We have the reference pK • a = 8.55 and as such can neglect the free energy of moving a (de)protonated residue from vacuum to water (Figure , left cycle). To determine the pK a we then need only consider the free energy difference of a deprotonation event in water and in the protein (Figure , right cycle).