The structure and function of most systems in nature depend heavily on non-covalent interactions between molecules. An examination of these Natural systems reveals that many of these molecules are amphiphilic and that their folding and assembly is driven by the hydrophobic effect. The broad, long-term goal of the research described in this proposal is to provide scientists with an improved understanding of the hydrophobic effect that will allow its use as a highly directional, specific, and predictable non-covalent interaction in water, much as hydrogen bonds and metal-ligand interactions are now used in chloroform. We work with a model system that comprises a series of water soluble self-complementary facial amphiphiles and study their self-association and recognition properties in water. We apply our model system to tackle two significant health related problems - namely the recognition of amino acids and short peptides like N-alpha-Ac-L-lys-D-ala-D-ala in water, and the selective inhibition of the formation of dimeric alpha-helical coiled coils like GCN4 that might be used to regulate DNA transcription and gene expression. We take an experimental approach based on synthetic organic chemistry and molecular modeling. We characterize our aggregates by multidimensional NMR, mass spectrometry, isothermal titration microcalorimetry, vapor pressure osmometry, and capillary electrophoresis.
The specific aims of our research are the following: 1 & 2) To use self-complementary facially amphiphilic derivatives of glycoluril to perform hydrophobic self-assembly in water. To determine the molecular level structural and thermodynamic details of these complexes and identify selective pairwise interactions that may be used to form well-defined thermodynamically stable (1 microM) aggregates in a predictable manner. 3) We will determine the energetic costs associated with changes in conformational entropy that occur during the """"""""folding"""""""" of dimeric facial amphiphiles in water 4 &5) We use complex non-natural facially amphiphilic oligomers to target the recognition of amino acids, peptides and protein surfaces in water.
| Isaacs, Lyle (2014) Stimuli responsive systems constructed using cucurbit[n]uril-type molecular containers. Acc Chem Res 47:2052-62 |
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| Chakrabarti, Sriparna; Mukhopadhyay, Pritam; Lin, Shirley et al. (2007) Reconfigurable four-component molecular switch based on pH-controlled guest swapping. Org Lett 9:2349-52 |
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| Lagona, Jason; Wagner, Brian D; Isaacs, Lyle (2006) Molecular-recognition properties of a water-soluble cucurbit[6]uril analogue. J Org Chem 71:1181-90 |
| Mukhopadhyay, Pritam; Zavalij, Peter Y; Isaacs, Lyle (2006) High fidelity kinetic self-sorting in multi-component systems based on guests with multiple binding epitopes. J Am Chem Soc 128:14093-102 |
| Wagner, Brian D; Boland, Patricia G; Lagona, Jason et al. (2005) A cucurbit[6]uril analogue: host properties monitored by fluorescence spectroscopy. J Phys Chem B 109:7686-91 |
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| Liu, Simin; Zavalij, Peter Y; Isaacs, Lyle (2005) Cucurbit[10]uril. J Am Chem Soc 127:16798-9 |
| Isaacs, Lyle; Park, Sang-Kyu; Liu, Simin et al. (2005) The inverted cucurbit[n]uril family. J Am Chem Soc 127:18000-1 |
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