Carboxyl–carboxylate interactions in proteins

Much of our present understanding of macromolecular architecture has come from the extrapolation to large molecules of rules derived from analysis of small molecules. This is exemplified by the work of Pauling et al.1 on polypeptide conformation, which depended on the insight afforded by the crystal structures of individual amino acids and some dipeptides. Now that accurate protein crystal structures are available, it appears that most of the hydrogen-bonding patterns that are observed have already been found in the structures of small molecules. Thus we can learn much about weak interactions in proteins by analysing small molecule crystal structures. Here we comment on the existence of hydrogen bonds between two carboxyl groups, forming what amounts to the acid salts of monobasic carboxylic acids. We believe these interactions are more important in stabilizing the structures of protein crystals and multi-subunit complexes at low pH than has been realized previously. Furthermore, the interaction contributes to hydrolytic activity and may be involved in inter-subunit recognition.