Hydrogen Tunneling in Enzyme Reactions

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9816791Dr. Klinman's work has been focused in two directions: expansion of the data base of proteins that utilize quantum mechanical behavior to accelerate the cleavage of C-H bonds and understanding the role of protein structure in this process. Increasingly the data point toward a revised view of enzyme catalysis in which we must move beyond a "classic" view of enzyme active sites. Such a "classic" picture depicts the protein catalyst as a "scaffold" for the presentation of multiple functional groups (cofactors, metals, amino acid side chains) to substrate; these groups then participate in a reduction in the height of the free energy barrier for the bond rearrangement steps. This picture must now be revised to include a role for proteins in modulating barrier width, as well as height, i.e.; the entire barrier shape is subject to modification as a means of providing rate acceleration. A second feature of "classic" catalysis is treatment of the enzymatic reaction barrier as a static entity. Increasingly there is evidence that a role for protein dynamical modes must be incorporated in modulating reaction barrier shapes and, hence, catalytic rate accelerations.Studies of the relationship between protein structure and function are fundamental to future advances in modern biochemistry and molecular biology. For example, use of mutagenesis to alter enzyme specificity and efficiency requires detailed understanding of the underlying paradigms for catalysis. The chemical industry has also begun to benefit from the emergence of designed catalysts which have the potential to expand reaction types and stereoselectivities beyond those found in naturally existing protein catalysts. Principles learned from studies of protein structure and function are directly applicable to the de novo design of biomemetic systems.