Project Summary Protein-mediated charge-transfer (CT) lies at the heart of energy processing in living systems [1, 2]. The chemistry of biocatalysis, oxidative stress, DNA synthesis and repair, and apoptosis all engage CT pathways [3, 4], and the malfunction of CT networks leads to disease. Understanding how CT pathways function - at the molecular, cellular, and multi-cellular levels - represents a grand challenge. And the principles emerging in this field promise to inform the development of future therapeutic strategies. Over the last decade, stunning discoveries were made in the emerging area of extracellular CT. The process of extracellular CT challenges our understanding of how living systems direct the flow of charge over very long distances. Organisms that recruit extracellular CT use poorly understood mechanisms, engaging extended multi- cofactor chains to accomplish long-range (!100 Å) CT. Extracellular CT is significant for many reasons: it arises in anaerobic infections, inter-species CT, and global bio-geochemical cycling [5, 6]. The strategies used by living systems to carry out very long-range CT are also of interest for developing novel bioderived power sources [7–10] and in fields that could benefit from making electrical interconnects between living and nonliving systems. While short distance intracellular CT reactions are relatively well understood, the conceptual and theoretical framework required to describe very long distance CT, including transport across multiple cells, is only beginning to emerge. The objective of this competing renewal proposal is to leverage our understanding of nanometer scale CT to elucidate the mechanisms of micrometer to centimeter scale biological CT. At large length scales, CT requires numerous cofactors and diverse protein structures. We aim to understand how structure and CT dynamics are linked at extremely long length scales in protein assemblies, where many CT steps must occur in long chains of redox active cofactors to realize biological function. We propose to study novel living systems that exploit long-range CT for function, namely bacterial nanowires and cable bacteria. We will use and expand a diverse toolbox of theoretical methods to understand the CT dynamics in these structures. Our research focuses on: (1) elucidating structure-function relationships that govern very long distance CT in bacterial nanowires; (2) establishing predictive models to describe very long-range CT in cable bacteria; (3) expanding and developing CT models to treat CT in multi-cofactor systems with fluctuating environments; and (4) establishing structure-function principles that govern CT across the range of length scales in biology, from nanometers to centimeters. Our studies involve close ties with experimentalists at the frontiers of CT research. Collaboration will continue to be a hallmark of this project, with involvement from experimental groups at the University of California - Irvine (Hochbaum), the ...