Disulphide bonds and protein stability

The properties of disulphide bonds relevant to their roles in stabilizing protein conformation are reviewed. Natural disulphides can stabilize folded conformations substantially, in some cases to much greater extents than would be expected from just entropic effects on the unfolded state. The linkage relationship between conformational stability and disulphide stability is illustrated. Disulphides will not, however, increase protein stability if the disulphides are not maintained in the unfolded state or if instability is caused by processes, such as chemical modification or proteolysis, that are not linked to unfolding, either local or global. This is part of the reason why some recent attempts to increase protein stability by introducing new disulphides have had only modest success. Other reasons appear to be the severe energetic constraints on disulphide bond geometry and, in some cases, unfavourable effects of introducing Cys residues by mutation.