Surface Recognition of a Protein Using Designed Transition Metal Complexes Md. Abul Fazal, Bidhan C. Roy, Shuguang Sun, Sanku Mallik,* and Kenton R. Rodgers Contribution from the Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105 ReceiVed August 28, 2000 Abstract: Each protein has a unique pattern of histidine residues on the surface. This paper describes the design, synthesis, and binding studies of transition metal complexes to target the surface histidine pattern of carbonic anhydrase (bovine erythrocyte). When the pattern of cupric ions on a complex matches the surface pattern of histidines of the protein, strong and selective binding can be achieved in aqueous buffer (pH ) 7.0). The described method of protein recognition is applicable to proteins of known structures. With rapidly increasing number of solved protein structures, the method has wide applicability in purification, targeting, and sensing of proteins. Strong and selective binding to a complex biomolecule in aqueous solution by synthetic receptors is an area of active research. 1 Molecules that bind to a particular protein with a high affinity have many potential applications including design of new and selective enzyme inhibitors, 2 design of stationary phases for chromatographic purification of proteins 3 and construction of protein sensors. 4 Recognition of an enzyme can be achieved by exploiting a structurally well-defined enzyme active site or a unique section of the protein’s surface topology. Each protein has a unique pattern of amino acid residues on the surface. It is this pattern that a surface receptor recognizes for binding and selectivity. Protein surface patterns can be recognized by polypeptides, 5 non-peptide charged moieties, 6 sugars, 7 etc. If the receptor binds on the surface of an enzyme close to the active site, this method can lead to efficient inhibitors 8a,b or disruptors for protein-protein interactions. 8c,d Combinatorial approaches to generate peptides and small molecules capable of binding to a protein have been demon- strated. 9 Linking two or more of these receptors improves the binding affinity and the selectivity by large increments. 10 Another approach for recognizing the surface pattern of amino acids of a protein involves template polymerization. 11 The methodology has been performed on a surface 12 or using a gel. 13 In this approach, a pattern complementary to that of the protein template is created on the polymer. We are interested in the recognition of peptides 14 and proteins 15 employing metal-ligand interactions. 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