The relationship of protein-ligand binding to pK a is of particular interest . Here, the pK a s of both the ligand and the binding site residues, as well as the pH-and bindinginduced conformational changes of the protein, are all intimately related. Resolving the precise states of the ionizable residues, as well as the local conformations of the apo and holo protein, are active fields of study that involve both experimental and computational approaches .