Computer Simulations of Electron Transfer Proteins

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DESCRIPTION (provided by applicant): One of the most intriguing questions about electron transfer proteins is how the protein modifies the electron transfer properties of its redox site. This knowledge is crucial in understanding the molecular basis of metabolic processes, diseases involving these processes, and drug design targeting these processes. The overall goal is to understand the properties of electron transfer proteins at a molecular level. The focus is on the iron-sulfur proteins, which are ubiquitous proteins involved in pathways as respiration, photosynthesis, and biosynthesis. Key issues we address are the stabilization by the protein of [4Fe-4S]3+/2+ in HiPIPs, [4Fe-4S]2+/1+ in ferredoxins, and [4Fe-4S]1+/0 in nitrogenase Fe-protein in aim 1, the intramolecular transfer in the "wire" of seven [4Fe-4S] clusters found in respiratory complex I in aim 2, and the Fe-S cluster assembly pathway in aim 3. Our approach uses continuum electrostatic calculations, molecular dynamics simulations, electronic structure calculations, and sequence and structural bioinformatics. An overriding aim in this period is to develop simple models that describe the architecture of metalloproteins with a few essential parameters based on our accumulated experience with these proteins. The models will be used to develop simple, fast software tools for predicting redox properties and metal binding sites of metalloproteins. In addition, these architectural models will be used in developing process models for protein-mediated electron transfer, which are essential for theoretical studies of large systems such as the respiratory complex I. Features of these models will be tested using other calculation techniques and experimental results from our collaborators. Moreover, these models will provide a framework for designing new calculations and experiments. The specific aims are: Aim 1. Develop an architectural model for reduction potentials of metalloproteins Aim 2. Develop models for protein-mediated electron transfer Aim 3. Develop models for conversion of Fe-S clusters in proteins PUBLIC HEALTH RELEVANCE: Computational studies of electron transfer proteins provide a fundamental, molecular understanding of the metabolic processes that move energy around living cells such as respiration and photosynthesis. This knowledge is crucial in understanding diseases that involve these processes and designing drugs to target these diseases. For instance, dysfunction in respiratory complex I has been associated with human neurodegenerative diseases and aging.