Fig. 4.13 For the contribution of a salt bridge to binding affinity, the environment in which this salt bridge is formed is crucial. In thrombin (left), the introduction of a benzamidine group 4.84.9 deeply buried in the S1 pocket leads to the formation of a salt bridge with Asp 189. The affinity gain is very large (see Fig. 4.11c). In the tRNA-guanine transglycosylase, the addition of a carboxylate group to the terminal phenyl ring 4.114.12 does not enhance the affinity of the nanomolar binding inhibitor 4.11. The crystal structure proves that the salt bridge to Arg 286 is formed geometrically. However, since it remains largely exposed to the surrounding solvent, its contribution is negligibly small.