Associate Professor of Biochemistry and Biophysics

Location: 236 Anatomy-Chemistry Building
Tel: (215) 573-3506
Fax: (215) 898-4217
Email: sharpk@mail.med.upenn.edu
Sharp Lab

Ph.D. University of British Columbia (1985)
 

DESCRIPTION OF RESEARCH INTERESTS: 
 

Dr. Sharp's general goal is to gain a detailed understanding of thestructure and function of proteins and nucleic acids at the molecular andphysical 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 behaviourof water and ions that solvate macro-molecules, which is as important asthe physical properties of the macro-molecules themselves.

Work in electrostatics has been concentrated on the development of ahybrid continuum model which includes a detailed description of the molecularstructure, the dielectric properties of molecule and solvent, and the effectsof ionic strength. This has been used to study the pattern of potentialsaround the enzyme superoxide dismutase, showing how the protein activesite focuses the electrostatic fields and enhances the enzyme rate thirty-fold.The role of electro-statics in shifting pKa's of ionizable amino acidsin thioredoxin has also been studied, and related to changes in stabilityupon mutation of these charged residues.

Work on the hydrophobic effect is focused on two areas: 1) Analysisof the thermodynamics of solvation, using simple nonpolar solute analoguesof amino acid side-chains as model compounds. This has recently led toa substantial increase (by a factor of 2 to 3) in our estimate of the strengthof hydrophobic stabilization of macro-molecular structure; 2) Understandingrecent experiments measuring the heat-capacity and hydrophobic solvationeffects in protein folding, and the effect of site directed mutagenesisof hydro-phobic residues upon protein stability.

RECENT REPRESENTATIVE PUBLICATIONS:

1. Sharp, K. (2001) Entropy-enthalpy compensation: fact or artifact?  Protein Sci.  10:661-667.
2. Prabhu, N. V., S.D. Dalosto,  K.A. Sharp, W.W. Wright and J.M. Vanderkooi (2002) Optical spectra of Fe(II) cytochrome c interpreted using molecular dynamics simulations and quantum mechanical calculations. J. Phys. Chem. 106:5561-5571.
3. Luo, H. and K.A. Sharp (2002). On the calculation of absolute binding free energies. Proc. Natl. Acad. Sci. USA (In press)
4. Manas, E., W. Wright, K.A. Sharp, J. Friedrich and J.A. Vanderkooi (2000) The influence of protein environment on the low temperature electronic spectroscopy of Zn substituted cytochrome c.  J. Phys. Chem. 104:6932-6941.
5. Chin, K., K.A. Sharp, B. Honig and A. Pyle (1999) Calculating electrostatic potentials of RNA: providing new insights into molecular interactions and function. Nature Struct. Biol. 6:1055-1061.
   
6. Kuntz, I.D., K. Chen, K.A. Sharp and P. Kollman (1999) The maximal affinity of ligands. Proc. Natl. Acad. Sci. USA 96:9997-10002.
7. Gallagher, K. and K.A. Sharp (1998) Electrostatic contributions to heat capacity Changes of DNA-ligand binding. Biophys. J. 75:769-776.

8. Sharp, K.A. and B. Madan (1997) The hydrophobic effect, water structure and heat capacity changes. J. Phys. Chem. 101:4343-48