P. LESLIE DUTTON, Ph.D.

Eldridge Reeves Johnson Professor of Biochemistry and Biophysics
Chair, Department of Biochemistry and Biophysics (1994-2008)
Director, Johnson Foundation for Molecular Biophysics
Fellow of the Royal Society

Location: 1005 Stellar-Chance Building
Tel: (215) 898-0991
Fax: (215) 573-2235
Email: dutton@mail.med.upenn.edu
Dutton's Lab

Ph.D. University of Wales (1967)

DESCRIPTION OF RESEARCH INTERESTS:

Dr. Dutton strives to understand elementary processes of oxidation-reduction and diverse biological events coupled to it, and to define the thresholds of oxidative failure potentiating pathogenesis.

Thirty percent of the nature's enzymes are oxidoreductases. They cover a wide range of biological functions including gene regulation, signalling, long range electron transfer, energy conversion (in photosynthesis and respiration), atom transport, drug detoxification, and a wide range of enzyme catalysis. Using a battery of physical, chemical and computational methods applied to a variety of oxidoreductases and redox proteins, the Dutton lab focuses on how biology controls the direction and speed of electron transfer with high fidelity over large distances through proteins: that is, which parameters drawn from quantum mechanical electron tunneling theory have been selected to engineer oxidoreductases.

Understanding electron tunnelling provides the foundation to investigate how biological redox reactions are coupled to the chemical events of proton exchange, protein conformation central to chemical catalysis signal transduction, and energy conversion.

In parallel to these investigations, the lab is exploring the possibility of synthesizing much simpler versions of the highly complex biological counterparts -- maquettes, constructed to reveal the minimal requirements for function. Work is aimed at designing protein that will self-assemble to incorporate porphyrins, chlorophylls, iron sulfur clusters, flavins, and quinones singly or together into synthetic protein. The goal is to understand the engineering of natural oxidoreductases and related enzymes to reproduce their action. Examples are photosynthetic reaction centers, phototactic signalling proteins, cytochrome oxidase, myoglobin, cytochrome P450, superoxide dismutase, ferredoxin and classical dehydrogenases. This interest extends to membrane associated oxidoreductase enzymes operate as the nanometer scale electronic units of respiratory and photosynthetic electron transfer chains that separate charges across the intracytoplasmic membranes.

RECENT REPRESENTATIVE PUBLICATIONS:

  1. Jones, A.K., Lichtenstein, B.R., Dutton, A., Gordon, G., and Dutton, P. L. (2007) Synthetic hydrogenases: Incorporation of an iron carbonyl thiolate into a designed peptide. J. Am. Chem. Soc. (Communication) 129:14844-14845.
  2. Koder, R.L., Lichtenstein, B.R., Cerda, J.F., Miller, A-F., and Dutton, P.L. (2007) A flavin analogue with improved solubility in organic solvents. Tetrahedron Letters 48:5517-5520.
  3. Dutton, P.L., Munro, A.W., Scrutton, N.S., and Sutcliffe, M. (2006) Introduction. Quantum catalysis in enzymes: Beyond the transition state theory paradigm. Phil. Trans. R. Soc B 361:1293-1294.
  4. Koder, R.L., Valentine, K.G., Cerda, J, Noy, D., Wand, A.J., and Dutton, P.L. (2006) Nativelike structure in designed four α-helix bundles driven by buried polar interactions. J. Am. Chem. Soc. (Communication) 128, 45:14450-14451.
  5. Moser, C.C., Farid, T.A., Chobot, S.E. and Dutton, P.L. (2006) Electron tunneling chains of mitochondria. Biochem. Biophysics Acta 1757:1096-1109.
  6. Moser, C.C., Page, C.C., and Dutton, P.L. (2006) Darwin at the molecular scale: selection and variance in electron tunneling proteins including cyctochrome c oxidase. Phil. Trans. R. Soc. B 361:1295-1305.
  7. Discher, B., Noy, D., Strzalka, J., Ye, S., Moser, C.C., Lear, J., Blasie, J.K., and Dutton, P. L. (2005) Design of amphiphilic protein maquettes: Controlling assembly, membrane insertion, and cofactor interactions. Biochemistry 44:12329-12343.
  8. Osyczka, A., Moser, C.C., Daldal, F., and Dutton, P.L. (2004) Reversible redox energy coupling in electron transfer chains. Nature 427:607-612.
  9. Page, C.C., C.C. Moser, X. Chen, P.L. Dutton (1999) Natural engineering principles of electron tunnelling in biological oxidation-reduction. Nature 402:47-52.
  10. Shifman, J.M., C.C. Moser, W.A. Kalsbeck, D.F. Bocian and P.L. Dutton (1998) Functionalized de novo designed proteins: Mechanism of proton coupling to oxidation/reduction heme protein maquettes. Biochemistry 37:16815-16829.
  11. Chen, X., Moser, C.C., Pilloud, D.L. and Dutton, P.L. (1998) Molecular orientation of Langmuir-Blodgett films of designed heme protein and lipoprotein maquettes. Journal of Physical Chemistry B 102:6425-6432.
  12. Gibney, B.R., S.E. Mulholland, F. Rabanal and P.L. Dutton (1996) Ferredoxin and ferredoxin-heme maquettes. Proc. Natl. Acad. Sci. USA 93:15041-15046.
  13. Robertson, D.E., R.S. Farid, C.C. Moser, J.L. Urbauer, S.E. Mulholland, R. Pidikiti, J.D. Lear, A.J. Wand, W.F. DeGrado and P.L. Dutton (1994) Design and synthesis of multihaem proteins. Nature 368:425-432.
  14. Moser, C., J.M. Keske, K. Warncke, R.S. Farid and P.L. Dutton (1992) Nature of biological electron transfer. Nature 355:796-802.