An Interfacial Thermodynamics Model for Protein Stability

Proteins are important macromolecules that exhibit thermodynamic and kinetic properties that are highly tuned to facilitate biological function within limited ranges of environmental conditions. Despite having a wealth of understanding of the interactions that affect protein stability [Dill, 1990; Pace, et al. 2004], such as the hydrophobic effect, hydrogen bonding, packing, solvation and electrostatic effects: Predicting thermodynamic properties of proteins is difficult because these interactions simultaneously work together within the molecular structure comprising of heterogeneous microenvironments that change dynamically as the conformational state of the protein changes. Consequently, a protein is truly a complex system [Bar-Yam, 1997] where thermodynamic and other emergent physical properties are sensitive to small perturbations in protein structure or its environment. It remains an open problem to develop models that can accurately predict protein stability, ligand-protein binding affinities and allosteric response, all of which are critical to the function of a protein [Petsko & Ringe, 2004; Klepeis, et al. 2004; Bray & Duke, 2004].