Two factors provide key contributions to the stability of thermophilic proteins relative to their mesophilic homologues: electrostatic interactions of charged residues in the folded state and the dielectric response of the folded protein. The dielectric response for proteins in a "thermophilic series" globally modulates the thermal stability of its members, with the calculated dielectric constant for the protein increasing from mesophiles to hyperthermophiles. This variability results from differences in the distribution of charged residues on the surface of the protein, in agreement with structural and genetic observations. Furthermore, the contribution of electrostatic interactions to the stability of the folded state is more favorable for thermophilic proteins than for their mesophilic homologues. This leads to the conclusion that electrostatic interactions play an important role in determining the stability of proteins at high temperatures. The interplay between electrostatic interactions and dielectric response also provides further rationalization for the enhanced stability of thermophilic proteins with respect to cold-denaturation. Taken together, the distribution of charged residues and their fluctuations have been shown to be factors in modulating protein stability over the entire range of biologically relevant temperatures.
Copyright 2004 Wiley-Liss, Inc.