We used free energy calculations within a continuum electrostatics model to analyze the coupling of protonation, reduction, and conformational change in azurin from Pseudomonas aeruginosa (PaAz). PaAz was characterized extensively with a variety, of experimental methods. Experimentally determined pK(a) values and pH-dependent reduction potentials are used to validate our computational model. It is well-known from experiment that the reduction of the copper center is coupled to the protonation of at least two titratable residues (His-35 and His-83) and to the flip of the peptide bond between Pro-36 and Gly-37. Free energy measures of cooperativity are used for a detailed analysis of the coupling between protonation, reduction, and conformational change in PaAz. The reduction of the copper center, the protonation of His-35, and peptide flip are shown to be cooperative. Our results show that cooperativity free energies are useful in detecting and quantifying thermodynamic coupling between events in biomolecular systems. The protonation of His-35 and the peptide flip are found to be so tightly coupled that these events happen effectively concerted. This concerted change results in a marked alteration of the electrostatic surface potential of azurin that might affect the interaction of azurin with its binding partners.