Stereoelectronics of Enzyme Catalysis

Molecules adopt geometries to facilitate effective delocalization—the basis of stereoelectronic effects. Functional groups with high-energy filled orbitals align themselves to communicate with those bearing low-energy unfilled orbitals. Furthering our understanding of stereoelectronic interactions within living systems provides a framework for the development of improved therapeutics, materials, and processes. In addition to our interest in the stereoelectronic control of bioorthogonal 1,3-dipolar cycloadditions, we are interested in elucidating interactions that control reactivity in living systems.

Aspartic proteases regulate many biological processes and are key therapeutic targets in the treatment of hypertension, HIV/AIDS, Alzheimer’s disease. We have recently revealed a stereoelectronic link between “the most obscure of all the proteases” and the oxyanion hole of serine proteases—the vivid illustration of nature’s catalytic strategy of transition state stabilization depicted in introductory biochemistry textbooks. This unique mode of enzyme catalysis both provides a new strategy for the rational design of therapeutics and expands the understanding of nature’s utilization of stereoelectronic interactions in enzyme catalysis.

See also:

Alabugin, I. V.; Gold, B. Stereoelectronic Effects: Origins and Consequences on Structure and Reactivity of Organic Molecules. in: Wang, Z. Encyclopedia of Physical Organic Chemistry; Wiley: Chichester, 2017.

Alabugin, I.V. Stereoelectronic Effects: A Bridge Between Structure and Reactivity. Wiley: Chichester, 2016.