The Mechanism of Sulfite Oxidase: A QM/MM Approach

Duke University, Durham NC

Investigators

Abstract

Sulfite oxidase (SO) catalyzes the physiologically essential reduction of sulfite to sulfate. This proposal uses the pseudobond QM/MM method to explore the mechanism of sulfite oxidase and, in particular, the long range electron transfer from the Mo center to the Fe center in sulfite oxidase. Particular issues to be addressed include the binding pattern of sulfite to the active site (is the activated complex bidentate?), the dissociation pathway of the sulfate product from the active site (SN1 or SN2?), the role of the Mo cofactor and the cysteine coordinated to the Mo, and the mechanistic importance of Argl38 and Tyr322 in chicken liver SO. Particular effort will be devoted to elucidating the mechanism of the rapid but long range (32 Angstroms) proton-coupled electron transfer between the Mo and the Fe centers. Understanding how the structure of the enzyme facilitates this electron transfer should provide valuable insight into mechanisms for long range electron transfer in biological systems and molecular wires. Due to the length of the electron transfer, a large portion of SO must be treated fully quantum mechanically: this necessitates methodological refinements of the pseudobond QM/MM procedure and, in particular, the development of efficient, linear-scaling, density functional theory and its incorporation into the QM/MM computer code. Finally, because electron transfers in SO are coupled to proton transfers, it is necessary to incorporate a method for the quantum mechanical treatment of protons into the QM/MM procedure. With these methodological refinements, pseudobond QM/MM can reveal mechanistic information not only for sulfite oxidase, but also for other electron and/or proton transfer systems.