SYNTHETIC BIS-METAL ION RECEPTORS FOR BIS-IMIDAZOLE PROTEIN ANALOGS

We are investigating an approach to protein recognition that is based on matching a pattern of metal ions in a synthetic receptor to a compl ementary pattern of metal-coordinating functional groups (histidine) o n a protein's surface. In this model study, target ''protein analogs'' were constructed by linking two imidazoles via organic spacers of var ying lengths. By computer modeling the individual targets and receptor s, bis-Hg2+ receptors were designed to position two metal ions to matc h the available nitrogen ligands of their target bis-imidazoles. While H-1 NMR studies in DMSO-d(6) show that the receptors can bind 2 equiv of 1-benzylimidazole (K-1 similar to 10(4) M(-1)), a bis-imidazole is bound in a 1:1 complex with association constants as high as 3 x 10(6 ) M(-1). Bis-metal ion receptors are indeed selective for their target bis-imidazoles in competitive binding experiments, preferring the tar get over others that are both longer and shorter by similar to 4 Angst rom (maximum selectivity = 11.5). A maximum selectivity of 140 was obs erved for the competition between a target bis-imidazole and 1-benzyli midazole. Increasing the available coordination sites on the metal ion significantly reduces selectivity, presumably by allowing the recepto r to take on multiple bound conformations. Attempts to improve binding selectivity by restricting the receptors' conformational mobility red uced selectivity, primarily by introducing unanticipated unfavorable i nteractions with the target bis-imidazoles.