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Christin Choma is focusing her
research on designing new, completely synthetic catalytic
proteins. Because proteins are complex polymers, designing
new proteins from scratch (de novo design) is very
challenging, but by taking a totally synthetic approach, Choma
can explore chemistries and functionalities not found in natural
enzymes. Unlike the process of trying to re-engineer a natural
protein for a novel application, she has complete control
over the size, shape, solubility, and activity of the designed
protein catalyst. One future application is the ability to
design enzymes with novel catalytic properties that are retained
in polluted environments. Success could mean an impact on
the bioremediation of land and water contaminated by the mining,
petroleum, and ore processing industries.
"The research is still at an early
stage," Choma said. "Although the synthesis of water-soluble
proteins is fairly straightforward, considerable innovation
has been required to find ways of synthesizing proteins that
are soluble in oils. We are designing small proteins that
can selectively oxidize a variety of compounds…[the]
goal is to lay the foundation so that the design of purpose-specific
enzymes will become a reality within the next 10 years. The
implications for the chemical, biotechnology, and pharmaceutical
industries are enormous."
Natural enzymes use a relatively
small number of functional and structural motifs to control
a wide range of biochemical reactions. The degree of selectivity
and versatility in this process is unequalled by non-protein
catalysts. The ability to design purpose-specific enzymes
tailored to specific substrates and environments will require
success in two areas. First, there will need to be an understanding
of how protein sequence subtly regulates the catalytic site
and protein structure. Secondly, the synthesis of novel prosthetic
groups or cofactors in order to impart unique catalytic functions
to proteins must occur. Choma is pursuing a direct approach
for achieving these goals. She is designing water-soluble
enzyme mimics consisting of a synthetic tetra-pyridyl iron-containing
prosthetic group having geometry and shape suited to interdigitating
between the helices of proteins. The purpose would be to enhance
the prosthetic group’s innate catalytic function. The
catalyst’s exposure to solvent, as well as the polarity
and dielectric constant of its binding site, are being varied
by systematically altering the sequence of the protein matrix.
The effect of these alterations both on the protein and on
the properties of the catalyst are first modeled using molecular
dynamics simulations. After synthesis, they are monitored
experimentally using physical-chemical techniques such as
potentiometry, NMR, and X-ray crystallography.
This project provides a new direction to
the field of de novo protein design, namely, the design
of synthetic enzyme mimics around non-natural prosthetic groups.
Success will require transcending traditional boundaries between
scientific disciplines by integrating polymer chemistry, molecular
modeling, heterocyclic chemistry, and biochemistry. Given
the increasing sophistication of proteins designed from first
principles and the utility of natural or chemically modified
enzymes in industrial processes, the tools and impetus for
designing new enzymes with unique characteristics specifically
for commercial or bioremediation purposes are at hand.
 Christin
T. Choma
Associate Professor, Department of Chemistry
Rensselaer Polytechnic Institute
110 8th Street
Troy, NY 12180-3590
(518) 276-2804
chomac@rpi.edu
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