Screening an Inverted Peptide Library in Water with a Guanidinium-Based Tweezer Receptor

A 1000-member, biased library of tripeptides, attached to TentaGel resin via the amino terminus, has been screened with dansyl-labeled tweezer receptor 4 in water. The tweezer receptor was found to bind to ∼3% of the library members and, following sequencing of 20 beads using a novel coding strategy, showed 95% selectivity for Val at the carboxy terminus of the tripeptides and 40% selectivity for Glu(OtBu) at the amino terminus. Although complicated by solubility issues, binding of one of the tripeptides selected from the screening experiments, Z-Glu(OtBu)-Ser(OtBu)-Val-OH, to tweezer 4 was measured by microcalorimetry to have an association constant, Kassoc = 4 × 105 ± 5 × 104 M-1 (in sodium borate buffer containing 16.7% DMSO, pH 9.2) and presumably results from a combination of a carboxylate−guanidinium interaction, β-sheetlike hydrogen bonding with the sidearms of the tweezer, and hydrophobic interactions.