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A total of fifty single site surface phenylalanine substitution mutants have been made in the model protein staphylococcal nuclease. The fifty residues that were replaced with phenylalanine were chosen to give a broad sampling of solvent accessibility, secondary structure, and backbone conformations. The change in the stability of each mutant protein relative to wild type was measured by guanidine hydrochloride denaturation. These results were compared to previous results obtained when these same sites were substituted with an alanine and a glycine. By this means, changes in the stability due to the loss of interactions of the wild-type side chain can be separated from the effects of introducing the bulky, hydrophobic phenylalanine in these solvent-exposed positions. In general, our results agree with the conventional wisdom that placing a hydrophobic residue in a solvent-exposed position is destabilizing in most cases, but less destabilizing than most changes in the hydrophobic core of the protein. However, the degree to which a hydrophobic surface substitution destabilizes or stabilizes a globular protein is highly context-dependent, with some mutations being as destabilizing as those in the core. This indicates that steric and packing considerations are also important on the surface of a globular protein but generally are not as important as in the interior. No evidence for the widespread occurrence of the so-called reverse hydrophobic effect at solvent-exposed sites was found. In addition, this survey of numerous sites suggests that previous measurements of alpha-helix "propensities" often seriously underestimate the importance of the environment of the side chain.
Schwehm et al. (Thu,) studied this question.