Experimental Approaches to Determine the Thermodynamics of Protein-Ligand Interactions

Used appropriately and judiciously, thermodynamic parameters can offer insight into the energetics of protein-ligand interactions that is not readily attainable by other means. The utility or application of thermodynamic analysis has traditionally been considered more the domain of (bio)chemistry than biology. However, the modern recognition of an interface in the case of protein-ligand interactions, particularly when the protein is an enzyme or a drug receptor, has kindled an integration with pragmatic benefit to basic understanding and to drug-discovery efforts [1]. Because the nature of most protein-ligand interactions involves relatively weak forces resulting from electrostatic attractions such as ion–ion, ion–dipole, dipole– dipole (hydrogen bonds), induced transient fluctuating dipoles (van der Waals), or hydrophobic effects, they are typically readily reversible and thus amenable to standard equilibrium thermodynamic analysis. Also convenient is that most protein-ligand interactions occur as closed systems, namely, they contain a fixed amount of matter, and the exchange of work is confined to expansion ( PdV). Because other types of energy exchange, such as radiation, or other types of exchange of work, such as electrical, surface, or photophysical, are negligible (or are approximated to be), the thermodynamic analysis of protein-ligand interactions is simplified. This chapter provides a broad overview of the purpose and experimental approaches for determining thermodynamic parameters of protein-ligand interactions.