PH-Dependent Free Energy Landscape, Conformational Selection, and Thermodynamics of Protein Folding

Abstract

Protein conformation change depending not only on the values of temperature, denaturant concentration but also on the values of solvent pH. The difference of the pH-denaturation from the thermal or urea denaturation is that hydrogen atoms (un)bind exclusively to R, K, Y, C, H, D, E amino acids. Thus the pH effect on the protein conformation is selective so that the physico-chemical machinery for the biological function of a protein frequently has its origin due to the solvent pH. Although several previous approaches were suggested to elucidate the (un)protonation behavior of a protein conformation, those were mainly oriented on evaluating pKa values of titratable residues in a given static protein conformation. The theoretical and calculation framework for describing the effect of solvent pH to the thermodynamic and kinetic properties of proteins under the equilibrium fluctuation is indispensable for the fundamental understanding of important biological phenomena of proteins.Here we present a development of the pH-dependent free energy function of proteins incorporating its equilibrium fluctuations based on the concept of statistical physics. The validity of our approach is justified by reproducing the experimental pKa values of titratable residues in several proteins. We also present the analytical and calculation framework for describing the pH-dependent thermodynamics and folding kinetics of proteins by the exact calculation. The effects of pH not only on the free energy landscape but also on the folding characters of several proteins are discussed.