EFFECTS OF SALT BRIDGES ON PROTEIN-STRUCTURE AND DESIGN

Theoretical calculations (Hendsch ZS & Tidor B, 1994, Protein Sci 3:21 1-226) and experiments (Waldburger CD et al., 1995, Nat Struct Biol 2: 122-128; Wimley WC et al., 1996, Proc Natl Acad Sci USA 93:2985-2990) suggest that hydrophobic interactions are more stabilizing than salt b ridges in protein folding. The lack of apparent stability benefit for many salt bridges requires an alternative explanation for their occurr ence within proteins. To examine the effect of salt bridges on protein structure and stability in mon detail, we have developed an energy fu nction for simple cubic lattice polymers based on continuum electrosta tic calculations of a representative selection of salt bridges found i n known protein crystal structures. There are only three types of resi dues in the model, with charges of -1, 0, or +1. We have exhaustively enumerated conformational space and significant regions of sequence sp ace for three-dimensional cubic lattice polymers of length 16. The res ults demonstrate that, while the more highly charged sequences are les s stable, the loss of stability is accompanied by a substantial reduct ion in the degeneracy of the lowest-energy state. Moreover, the reduct ion in degeneracy is greater due to charges that pair than for lone ch arges that remain relatively exposed to solvent. We have also explored and illustrated the use of ion-pairing strategies for rational struct ural design using model lattice studies.