George M. Whitesides

Department of Chemistry & Chemical Biology
Harvard University
Mallinckrodt Building, Room 229
12 Oxford Street, Cambridge, MA 02138

tel: (617) 495-9430; fax: (617) 495-9857
email: gwhitesides@gmwgroup.harvard.edu
web: http://gmwgroup.harvard.edu

Bio-organic and Biophysical Chemistry

Carbohydrate Biochemistry. We are involved in a range of projects in glycobiochemistry. In one, we are developing synthetic routes to carbohydrates of interest in biochemistry and medicine. We commonly use any appropriate combination of enzymatic catalysis and classical organic synthesis. The area of carbohydrate chemistry is one of the most interesting and least explored areas of modern biochemistry. Carbohydrates are ubiquitous in biology, with the functions ranging from recognition and signaling to structure and energy storage. We contribute synthetic methods and reagents to this area, and prepare and test biologically active carbohydrates.

Rational Drug Design. The use of physical organic chemistry to understand the structural basis for molecular recognition in biochemistry, and the application of this understanding to the design and synthesis of active-site specific binding agents, is one of the most important opportunities in pharmaceutical/medicinal chemistry. We are developing a number of paradigms combining synthesis, physical-organic chemistry, protein chemistry and computation to try to understand how to rationalize and exploit molecular recognition in biological contexts. The two model systems with which we are presently most concerned are carbonic anhydrase (which binds sulfonamides in their anionic form to an active site zinc) and the influenza hemagglutinin (which recognized sialic acid on the mammalian cell surface).

These problems are interesting for different reasons: the former is a prototypic problem in active site inhibition; the latter is a problem in polyvalent interaction between extended biological surfaces. Both have the 'simplicity' required for detailed physical-organic studies. An important component of this project is the development of efficient new techniques for measuring binding. Capillary affinity electrophoresis is one such technique.

Computation: Neural Networks and Molecular Mechanics. We are developing methods for applying a new form of computational pattern recognition- neural network computation- to molecular recognition. We use molecular mechanics and dynamics routinely as a tool to aid design in biochemical problems.

Biomimetic surfaces. By preparing self-assembled monolayers, we have a route to what are essentially quasi-two dimensional crystals on appropriate surfaces (most commonly in our work, gold). Using the SAMs derived from fatty acids, and functionalizing these at the terminus with biologically relevant ligands, we can prepare surfaces in which these complex ligands decorate the solid-water interface. These systems are, we believe, excellent structural mimics of cell membranes. Our particular interests in this area have to do with the physical-organic chemistry of adsorption of enzymes and oligosaccharides at the solid-water interface, and of association/recognition phenomena at this interface.

Selected Publications:

Chin, D.N., Gordon, D.M., Whitesides, G.M. (1994). Computational Simulations of Supramolecular Hydrogen-bonded Aggregates: HubM2, FlexM3, and Adamantane-based Hubs in Chloroform. J. Am. Chem. Soc. 116:12033-12044

Abbott, N.L., Gorman, C.B., Whitesides, G.M. (1995). Active Control of Wetting Using Applied Electrical Potentials and Self-Assembled Monolayers. Langmuir 11:16-18.

Gorman, C.B., Biebuyck, H.A., Whitesides, G.M. (1995). Use of a Patterned Self-Assembled Monolayer to Control the Formation of a Liquid Resist Pattern on a Gold Surface. Chem. Mat. 7:252-254.

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