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) reactions are essential processes in biological systems, fundamental to various enzymatic functions and redox biology. Key to these reactions are redox-active residues, such as tyrosine and tryptophan, which enhance the efficiency and specificity of electron transfer events. This thesis investigates the thermodynamics, kinetics, and conformational influences of PCET in proteins involving these residues through three projects, each offering significant insights into the mechanisms and broader implications for biological function. The studies have focused on two protein systems: a simple de novo protein system, α3X, and ribonucleotide reductase, an enzyme critical to DNA synthesis. Combining a wide range of computational chemistry methods and theoretical frameworks, this thesis elucidates the critical roles of redox-active protein residues in PCET reactions that could be challenging to characterize experimentally. Through comprehensive studies of noncanonical amino acid redox potentials, kinetic and mechanistic analyses of PCET reactions, and an in-depth assessment of hydrogen tunneling and conformational motions in RNR, this research significantly advances our understanding of these complex biochemical phenomena. These insights enhance our foundational knowledge of PCET and redox chemistry in proteins, guiding the design of biomimetic catalysts and innovative therapeutic interventions.

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