296 Modular Self-Assembled Receptors for Peptides

Thursday, November 5, 2009: 11:40 AM
Ballroom C+D (Camino Real Hotel)
Adam R. Urbach , Department of Chemistry, Trinity University, San Antonio, TX
In an effort to model the behavior of multivalent receptors in biological systems, we have developed a biomimetic approach to the synthesis of modular, multivalent receptors in aqueous solution by molecular self-assembly.  Our system is based on the synthetic macrocycle, cucurbit[8]uril (Q8), which has the unusual characteristic that it binds selectively and tightly to two different guests in aqueous solution.  Q8 binds first to methyl viologen, and the resulting Q8•MV complex binds to tryptophan-containing peptides in a sequence-selective manner, preferring N-terminal tryptophan on the basis of electrostatic charge. The simultaneous inclusion of viologen and indole groups within the cavity of Q8 leads to the quantitative formation of a new visible charge-transfer absorbance and quenching of indole fluorescence. We have made use of the unique properties of this system to overcome the difficulties inherent to synthesizing and characterizing multivalent receptors.  Instead of covalently linking the two hosts, we use the auxiliary viologen guest as a handle.  Peptide-based scaffolds presenting 1–3 viologen groups were prepared and found to bind noncooperatively to a respective 1-3 copies Q8.  The resulting self-assembled mono-, di-, and trivalent receptors bind to their cognate target peptides containing 1-3 tryptophan residues with Ka values in the range 1.7 x 10^4 to 4.7 x 10^6 and in predictable mono- or multivalent binding modes with increased affinity and additive enthalpies due to multivalency.  Although it is often difficult to determine the number of simultaneous interactions in a multivalent complex, the extent of valency in our system was determined directly by measuring the visible charge-transfer absorptivity due to the viologen-indole pair.  The favorable binding properties of this system combined with economical synthesis and analysis make it well suited to serve as a model for multivalent binding and for the multivalent recognition of peptides by design.