Towards a quantum-mechanical understanding of proton-coupled electron transfer and transition metal reactivity in biological processes

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Project Summary/Abstract A fundamental understanding of biological processes is necessary to further the advancement of therapeutics and technologies that will benefit human health. In principle, the laws of quantum mechanics hold the key to such an understanding, with the potential to reveal (with the highest resolution possible) every detail of physiological processes that occur naturally in biological systems, and relevant mechanisms of action that can be harnessed to combat disease and improve health. In practice, however, despite rapid advances, state-of-the-art methodologies for investigating quantum phenomena are still rather limited, as experimental techniques face difficulties of resolution and interpretive ambiguities while exact theoretical predictions require computational effort which grows exponentially with system size. This proposal aims to utilize and further develop promising computational methods, to be used in concert with experimental techniques, to provide unprecedented insights into proton-coupled electron transfer (PCET) processes and the catalytic ability of transition metals that occur naturally in biology. The first proposed research aim involves the combination of two-dimensional electronic vibrational spectroscopy and excited-state electronic structure calculations to probe the ultrafast PCET dynamics in a biomimetic, synthetic model compound of Photosystem II. This work will yield general insights regarding the PCET motif which is ubiquitous in human biology, and which plays a critical role in diseases such as Amyotrophic Lateral Sclerosis. The second aim will develop an efficient computational protocol to accurately predict the binding affinity of potential drug candidates into protein sites that contain transition metal ions. This technology will nearly double the number of druggable targets that can be tackled with rational drug design platforms, and will accelerate the discovery of a wide range of new therapeutics. The third research aim seeks to investigate the multireference electronic structure of metal complexes with non-innocent ligands, in particular the motif of heme binding to O2 as found in oxygen transport and the catalytic cycle of cytochrome P450, and to model the redox activity of multi-metal systems containing iron and sulfur atoms. This research will be performed with the guidance of Martin Head-Gordon as sponsor and Graham Fleming as collaborator, both Professors of Chemistry at University of California, Berkeley (UCB). The proposed training plan will take advantage of the diversity of expertise and stimulating environment at UCB, with synergies present across labs, departments, and affiliated institutions. The plan for career development involves the opportunity to mentor graduate students, and to develop teaching, public speaking, and grant-writing skills that will help me to achieve the goal of becoming a leader of a research group, joining a community of scientists from all backgrounds to solve pressing problems that will lead to the improvement of health.