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KIM A. SHARP, Ph.D.

Associate Professor of Biochemistry and Biophysics

805A Stellar-Chance Labs
422 Curie Blvd.
T: (215) 573-3506
F: (215) 898-4217
sharpk@mail.med.upenn.edu

Sharp Lab

Ph.D. University of British Columbia (1985)

pubmed

DESCRIPTION OF RESEARCH INTERESTS:

Dr. Sharp's general goal is to gain a detailed understanding of the structure and function of proteins and nucleic acids at the molecular and physical chemical level using theoretical and computational methods.

Two of the fundamental interactions in macromolecules are electrostaticsand the hydrophobic effect. Both require an understanding of the behaviour of water and ions that solvate macromolecules, which is as important as the physical properties of the macromolecules themselves.

Work in electrostatics has been concentrated on the development of a hybrid continuum model which includes a detailed description of the molecular structure, the dielectric properties of molecule and solvent, and the effects of ionic strength. This has been used to study the pattern of potentials around the enzyme superoxide dismutase, showing how the protein active site focuses the electrostatic fields and enhances the enzyme rate thirty-fold.The role of electro-statics in shifting pKa's of ionizable amino acids in thioredoxin has also been studied, and related to changes in stability upon mutation of these charged residues.

Work on the hydrophobic effect is focused on two areas: 1) Analysis of the thermodynamics of solvation, using simple nonpolar solute analogues of amino acid side-chains as model compounds. This has recently led to a substantial increase (by a factor of 2 to 3) in our estimate of the strength of hydrophobic stabilization of macromolecular structure; 2) Understanding recent experiments measuring the heat-capacity and hydrophobic solvation effects in protein folding, and the effect of site-directed mutagenesis of hydrophobic residues upon protein stability.

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