Dissertation Defence: Free Radical Generation and Control in Radical S-Adenosylmethionine (SAM) Enzyme Catalysis

M. Hossein Khalilian, supervised by Dr. Gino A. DiLabio, will defend their dissertation titled “Free Radical Generation and Control in Radical S-Adenosylmethionine (SAM) Enzyme Catalysis” in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry.

An abstract for M. Hossein Khalilian’s dissertation is included below.

Examinations are open to all members of the campus community as well as the general public. Registration is not required for in-person exams.

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Abstract

There are thousands of radical S-adenosylmethionine (rSAM) enzymes capable of catalyzing over 80 distinct reactions, yet their use in biotechnological applications is limited, primarily due to a lack of understanding of how these enzymes control highly reactive radical intermediates. This work demonstrates that little-known quantum Coulombic interactions are, in part, responsible for free radical control in viperin/RSAD2, one of the few radical SAM enzymes expressed in humans. Through molecular dynamics and multi-state broken-symmetry quantum mechanical/molecular mechanics calculations (QM/MM), both the mechanism and radical control in catalysis were elucidated, revealing a key step characterized by the formation of an unusual metastable deprotonated ribose radical intermediate. This intermediate is thermodynamically stabilized by spin-charge exchange-correlation interactions—a quantum Coulombic effect. The magnitude of this stabilization is such that the radical displays acidity two to six pKa units lower than that of closed-shell ribose. Given the omnipresence of charges in biological systems, these interactions potentially represent a universal mechanism for stabilizing and controlling highly reactive radical intermediates across radical enzymes, opening new avenues for enzymatic engineering and biotechnological applications.