Hemoglobin acts as a receptor for a variety of small molecular weight compounds. Some of these have potential as anti-sickling agents or agents that promote delivery of oxygen, but so far their practical application has foundered on their strong affinity for serum albumin. The stereochemistry of binding of these molecules to the recently solved structure of serum albumin will be explored with a view to modifying their structure so as to lower their affinity for albumin without lowering the affinity for hemoglobin. Work on the binding of potential anti-sickling compounds to hemoglobins has led to the finding that these compounds seek out niches in the protein that fit their van der Waals shape, and that within those niches the compounds arrange themselves so as to maximize the electrostatic interaction between drug and protein. Recent experience has shown that this rule is far from sufficient to allow us to predict where these molecules will bind to different sites in the protein. Most receptors are large membrane proteins of as yet unknown structure. Hemoglobin is an ideal model receptor for exploring the rules that govern small molecular to proteins. Human globin can now be made in E.coli. This has opened the way to directed mutagenesis of hemoglobin, and this will allow an exploration of the evolution of the hemoglobin structure and of its specialized functions in different species. One possible strategy towards the prevention of sickling would be inhibition of the phosphoglyceromutase that converts 1,3- to 2,3- diphosphoglycerate. Horseradish peroxidase is widely used in diagnostic tests and could be adapted to more uses by directed mutagenesis, but its structure is unknown. Efforts are under way to determine the structures of both these proteins.
