The foci of this research are two fold. First, synthesis will be used to prepare examples of small molecule receptors that precedent suggests will be selective peptide binders and then screening them for binding with combinatorial libraries of ca. ten thousand different tri- or hexapeptides. Receptor designs that show high sequence selectivity will then be used as the basis of libraries of receptors. Second, new simulation methodology will be developed to deal with the sampling problem involved in averaging the populated states of a complex molecular system, in particular, a molecular system having many distinct, low energy forms or conformers. The methods developed will be used to predict relative binding free energies of different substrates for a given receptor. With this renewal award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. W. Clark Still of the Department of Chemistry at Columbia University. Dr. Still will focus his work on the design and preparation of synthetic, small molecule receptors for complex biological and chemical substrates. Such small molecule receptors have potential value both in understanding the basis of molecular recognition and in practical applications involving chemical sensing, chemical separations and catalysis. The research employs two different approaches: one experimental that uses combinatorial methods in receptor design and one theoretical that involves calculations of free energies.
