Towards a Quantum-Mechanical Understanding of Redox Chemistry in Proteins - Project Summary/Abstract Metals are found in almost every protein that serves a biological function, and understanding their role in the chemical reactions that guide metabolism and respiration is critical to improving outcomes for a number of genetic diseases and for identifying new therapeutic drug targets. These metal-containing proteins (metalloen- zymes) are amenable to study via x-ray spectroscopy, which can elucidate the behavior of electrons during metal-catalyzed chemical reactions and, when paired with quantum chemistry calculations, a deep under- standing of the reaction pathways. Quantum chemistry provides the most nuanced and detailed picture of the chemistry of electrons in all of science, allowing for models of unparalleled insight to be constructed. While ad- vances in synchrotron light sources have pushed experimental x-ray spectroscopy into the future, methods for computational x-ray spectroscopy have not yet achieved a sufficient balance of efficiency and accuracy for the study of metalloenzymes. The work proposed herein will pursue a suite of accurate and efficient computational x-ray spectroscopy methods based on quantum chemistry. Recent developments in time-dependent density functional theory will be extended to properly deal with the unpaired electrons that typify the metal centers within metalloenzymes. This approach will then be used alongside cutting-edge wave function analysis meth- ods in quantum chemistry to determine whether copper atoms ever adopt a 3+ oxidation state in the reaction mechanism of tyrosinase. The existence, or lack thereof, of Cu(III) in vivo is critical to guiding our chemical un- derstanding of metalloenzyme reactivity, but its presence has yet to be directly identified in biological systems. To carefully address this question, additional methods will be designed using more theoretically rigorous wave function theory (WFT), thus avoiding potential errors imposed by approximations inherent to density functional theory and giving access to the L-edge part of the x-ray spectrum. Combined, these methods will achieve the most comprehensive computational characterization of copper intermediates in metalloenzyme reaction pathways reported to date. This computational analysis will simulate the x-ray, resonance Raman, and opti- cal absorption spectra that will be collected by experimental collaborator, Ed Solomon (ES). After addressing the question of Cu(III), additional investigations into iron(IV)-oxo intermediates will be pursued with a similar protocol. With the combined insights of quantum chemistry and empirical data, the identity of the chemical intermediates in metalloenzyme catalysis will finally be revealed. A highly collaborative environment at Uni- versity of California, Berkeley (UCB) will allow for frequent interactions with world-class researchers. The proposed research will be carried out under the guidance of Martin Head-Gordon and with the assistance of ES at Stanford University. The career training plan includes mentoring graduate students, teaching courses, attending workshops on accessibility in research environments and grant-writing, networking, and performing community outreach. This training plan will build a strong foundation for a career in health-related research.
