Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Hammes-Schiffer, Sharon

Abstract

Proton-coupled electron transfer (PCET) is a fundamental chemical process where both an electron and a proton are transferred simultaneously or sequentially, playing a key role in various biological and chemical systems, including enzymatic reactions and energy conversion. This thesis investigates the PCET reactions in ribonucleotide reductase (RNR), a critical enzyme responsible for DNA synthesis and repair in all living organisms. While significant progress has been made in understanding RNR's PCET pathway, several gaps remain, particularly regarding the specific mechanisms and energetics of individual PCET steps, the role of conformational dynamics, and the influence of water molecules. Through quantum mechanical/molecular mechanical (QM/MM) free energy simulations and PCET theories, this work provides detailed insights into four PCET reactions throughout the α2 subunits. The results show that the electrostatic interactions between tyrosines, cysteine, glutamate, and water significantly lower the free energy barrier and reaction free energies. Additionally, this study examines the impact of nonadiabatic effects by analyzing the vibronic and electron-proton nonadiabaticities of these reactions. We focused on the direct PCET between Y356 and Y731, calculating its rate constant and highlighting the roles of hydrogen tunneling and conformational motions in this interfacial PCET. Our work enhances the understanding of PCET in RNR and provides valuable insights for future protein engineering efforts to modulate RNR activity for therapeutic purposes. Furthermore, this research contributes to the broader computational community by advancing methods for modeling large-scale systems.

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