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Neil Marsh

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Primary Appointment: LSA Chemistry
Other PIBS Depts.: Biophysics
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 DESCRIPTION OF RESEARCH
  My laboratory focuses on two areas of chemical biology. In one area, we seek to understand the remarkable catalytic prowess of enzymes, in particular those that use free radicals in catalysis. In a second research area we are exploring the potential for developing novel biological catalysts and therapeutic agents offered by the de-novo design and synthesis of novel proteins incorporating highly fluorinated amino acids. Our research is inherently inter-disciplinary in nature and draws on a synergistic combination of bio-organic, bio-inorganic and bio-physical chemistry.

One major interest is in enzymes that use free radicals (a carbon with an unpaired electron) to catalyze a variety of unusual reactions, many of which have no ready counterpart in organic chemistry. Normally, organic radicals are thought of as highly reactive species that are dangerous to biological systems. However, enzymes can profoundly alter the reactivity of free radicals so that a radical with a lifetime of microseconds in free solution may be stable for days when generated within a protein! Enzymes are therefore able to exploit free radicals as 'sparks' with which to ignite reactions on otherwise un-reactive substrate molecules.

We are studying two types of radical enzymes: one that uses the cobalt-containing organo-metallic coenzyme B12 to generate free radicals and another that uses S-adenosylmethionine (SAM) to generate radicals. These enzymes provide excellent model systems with which to study free radical catalysis. We are using a variety of kinetic and spectroscopic techniques, together with site-specific mutagenesis to understand how the enzymes generate and control reactive organic radical species.

In a second area of research, we are exploring the interface between biological macromolecules and materials chemistry though the de-novo design of extensively fluorinated 'Teflon' proteins. Perfluorocarbons exhibit unique and useful physical properties that are not found in nature. For example, Teflon derives its highly inert and non-stick properties from the perfluorinated polymer polytetrafluoroethylene. We are examining the effects of replacing 'greasy' hydrophobic amino acids that are found in the interior of proteins with extensively fluorinated analogs to create a 'Teflon' interior. We have shown that such proteins exhibit useful new properties such as increased thermal stability, resistance to unfolding in organic solvents, and resistance to degradation by proteases. Teflon proteins may also exhibit novel protein:protein interactions and provide model systems to test theories of protein folding.

Recently we have begun to apply what we have learned from studying de-novo designed "Teflon" proteins towards the modification the properties of naturally occuring antimicrobial peptides. These peptides form part of the innate immune system and our studies hold promise for the design of more effect antibiotic and antiviral treatments.