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Understanding protein-ligand binding thermodynamic parameters is fundamental for rational drug design. However, despite the importance, due to the complexity of protein-ligand systems, areas of this field, including volume change due to protein-ligand binding (Vb) and ionic interaction, are left largely unexplored. This thesis researches the volumetric characteristics of protein-ligand binding in carbonic anhydrase (CA)-sulfonamide model systems. CA XIII unfolding pathway using guanidinium hydrochloride (GdmHCl) was determined for the first time. The relationship between melting pressure (Pm) and GdmHCl concentration was evaluated for CA I, CA II, and CA XIII. A concept of fluorescent pressure shift assay technique using different GdmHCl and ligand concentrations for strong ligand Vb determination was proposed. The high-pressure NMR technique was employed to determine Vb values of primary sulfonamide inhibitor binding to CA I and CA II. A method for determining changes in volume upon protein-ligand binding from a single series of NMR spectra was described for the first time.A model system consisting of oppositely charged amino acid homopolymers and surfactants was used to determine the contributions of chemical modifications and ionic interaction toward protein-ligand binding. Contributions of alkyl chain and head group make-up towards enthalpy and heat capacity of interactions were determined for the first time in an oppositely charged poly(amino acid)- surfactant system.