Solomon, Lee Andrew

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  • Publication
    The Physical Chemistry Underlying the Assembly and Midpoint Potential Control in a Series of Designed Protein-Maquettes
    (2013-01-01) Solomon, Lee Andrew
    In nature, oxidoreductase proteins are responsible for many enzymatic processes critical to life. These proteins often rely on the presence of non-proteinaceous cofactors to take part in the enzymatic function. The most common, central to my thesis, is heme B. Depending on the protein environment, this cofactor can take part in functions as diverse as electron transfer (cytochromes), oxygen transport (hemoglobins), oxygen reduction (oxidases), carbon-hydroxylation (oxygenases), and superoxide production (NADH oxidase). In natural oxidoreductases, determination of the course and rates of heme-protein association, what barriers are encountered, what affinity is achieved, and what are the oxidation-reduction potentials, is critical for understanding the rules of assembly and function of the different activities performed. In the growing field of research attempting to make man-made oxidoreductases, the same understanding is required for progress to be made toward construction of novel enzymes. However, this understanding is still out of reach in natural oxidoreductases because of the immense complexity of natural proteins, while for man-made designs progress has only recently reached a point where an in-depth systematic study can be contemplated. My thesis states: Simple non-natural proteins (maquettes) designed from first principles to ligate heme, can be used to uncover the factors derived from the oligomeric and structural state of related maquette and also derived from porphyrin variants of heme B, that govern rates of incorporation and ligation of heme B into a maquette. Maquettes are ideal platforms to demonstrate what aspects of a protein govern heme redox potentials, a key parameter underlying the diversity of hemoprotein functions. The findings from my work provide the first views of heme and maquette assembly: spontaneous, rapid and with high affinity association. They also provide a foundation for understanding what controls redox potentials of the heme and perspective on this control. The work offers insight into similar processes in natural oxidoreductases, but the concepts and principles uncovered in this thesis will be vital in the development of novel functions applied in man-made applications in vitro and in vivo.