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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM061854-01S1
Application #
6337648
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2000-09-01
Budget End
2001-05-31
Support Year
1
Fiscal Year
2000
Total Cost
$32,808
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742
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
Wang, Zhi-Guo; Zhou, Bao-Han; Chen, Yun-Feng et al. (2006) Substituent effects control the self-association of molecular clips in the crystalline state. J Org Chem 71:4502-8
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
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
Lagona, Jason; Fettinger, James C; Isaacs, Lyle (2005) Cucurbit[n]uril analogues: synthetic and mechanistic studies. J Org Chem 70:10381-92
Liu, Simin; Ruspic, Christian; Mukhopadhyay, Pritam et al. (2005) The cucurbit[n]uril family: prime components for self-sorting systems. J Am Chem Soc 127:15959-67

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