Thus mutation of a residue with only indirect support of catalytic function may devastate function and seem to be of central importance. 21,22 Previously independent amino acid residues came to depend upon one another for continued function. This is because natural selection has an inherent tendency to create systems in which component parts become progressively interdependent 19,20-the protein-level equivalent to Muller's genetic ratchet. While mutation of individual residues can verify their functional importance, mutation imperfectly clarifies the residue's role. 18 Here, the complexity of natural bioenergetic protein structures obscures which engineering elements are critical for function and which elements may be incidental remnants of an evolutionary legacy. However, factors other than electron-tunnelling distance can dominate performance, especially at the catalytic centres terminating electron-transfer chains. 13,14 By constructing a matrix of electron-tunnelling rates between all redox centres in a protein, we can model the progress of electron transfer to reveal the relative weaknesses and strengths in natural electron-transfer chain design. A survey of dozens of individual bioenergetic electron-transfer reactions, both productive and unproductive, using both natural and unnatural redox centres, has shown that a relatively simple formula depending on only three parameters captures the quantum mechanics adequately to provide estimates of electron-tunnelling rates within an order of magnitude. Indeed, such structures have provided a good appreciation of how electrons tunnel from one redox centre to another across the intervening electrically insulating protein medium to form chains of redox centres that connect catalytic centres of bond breaking and making. 1–12 Such atomic resolution offers the promise of a detailed understanding of how these naturally evolved systems function to direct electron and proton transfer to support life, or how they may dysfunction in disease. Furthermore, these practical understandings allow us to go beyond natural protein designs that are dedicated to natural cellular needs, to engineer robust novel electron-transfer systems directed instead towards human needs such as solar energy trapping in renewable fuels.Įxtensive work developing X-ray crystal structures of core natural bioenergetic proteins exposed the arrangement of hundreds to thousands of amino acids that surround and bind a range of different cofactors that support bioenergetic light absorption and respiratory and photosynthetic electron and proton transfer. Such designs allow reverse engineering of natural proteins to separate out protein elements that are important for function from those that are remnants of the legacy of evolution. University of Pennsylvania, Johnson Research Foundation, Department of Biochemistry and Biophysics, Philadelphia, PA, USA.Į-mail: practical understanding of first-principles directed protein folding in de novo protein design and the factors that control intraprotein electron tunnelling in both natural and artificial proteins allows the planned design of artificial counterparts of natural bioenergetic proteins. 1-24Ĭhemical Biology Chapter 1 Making Maquette Models of Bioenergetic Structures Dutton, Chapter 1:Making Maquette Models of Bioenergetic Structures, in Mechanisms of Primary Energy Transduction in Biology, 2017, pp.
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