Electrostatic contributions to protein stability and folding energy.

The ability to predict the thermal stability of proteins based on their corresponding sequence is a problem of great fundamental and practical importance. Here we report an approach for calculating the electrostatic contribution to protein stability based on the use of the semimacroscopic protein dipole Langevin dipole (PDLD/S) in its linear response approximation version for self-energy with a dielectric constant, (epsilon(p)) and an effective dielectric for charge-charge interactions (epsilon(eff)). The method is applied to the test cases of ubiquitin, lipase, dihydrofolate reductase and cold shock proteins with series of epsilon(p) and epsilon(eff). It is found that the optimal values of these dielectric constants lead to very promising results, both for the relative stability and the absolute folding energy. Consideration of the specific values of the optimal dielectric constants leads to an exciting conceptual description of the reorganization effect during the folding process. Although this description should be examined by further microscopic studies, the practical use of the current approach seems to offer a powerful tool for protein design and for studies of the energetics of protein folding.