Study of electrostatic effects on protein folding and binding stabilities

The electrostatic effects of 113 charge mutations on the folding stabilities of 8 different proteins were studied by carrying out the continuum electrostatic calculations. Instead of the widely used solvent-exclusion (SE) surface, we used the van der Waals (vdW) surface as the boundary between the protein and solvent dielectrics. The calculated effects were directly compared with the experimental results and the calculations using SE surface. In general, vdW surface did better work than SE surface. We conclude that: (1) the popular view that electrostatic interactions are generally destabilizing may have been based on overestimated desolvation cost as a result of using the SE surface as the dielectric boundary; (2) while solvent-exposed charges may not reliably contribute to protein stability, semi-buried salt bridges can provide significant stabilization; (3) the good correlations between the calculated results using van der Waals surface and the measurements (0.98 correlation for 27 mutations on cold shock protein, 0.7 correlation for 52 mutations on staphylococcal nuclease, and 0.8 correlation for 34 mutations on other 5 proteins) suggest electrostatic interaction make significant contributions to protein folding stabilities.; In addition, the electrostatic effects of 80 mutations on the binding stabilities of 6 different complexes were also studied. Three different protocols were used: (a) the dielectric boundary specified as the van der Waals (vdW) surface of the protein along with a protein dielectric constant (epsilon p) of 4; (b) the dielectric boundary specified as solvent exclusion (SE) surface along with epsilonp = 4; and (c) "SE + (epsilonp = 20)". The "vdW + (epsilonp = 4)" and "SE + (epsilonp = 4)" protocol predicted an overall electrostatic destabilization. The "vdW + (epsilonp = 4)" protocol was most consistent with experiment. At the very least, this study demonstrates that caution is required in drawing conclusions on electrostatic contributions based on a particular Poisson-Boltzmann calculation protocol.