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Identifying sequence determinants of reduction potentials of metalloproteins

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Abstract

The reduction potential of an electron transfer protein is one of its most important functional characteristics. Although the type of redox site and the protein fold are the major determinants of the reduction potential of a redox-active protein, its amino acid sequence may tune the reduction potential as well. Thus, homologous proteins can often be divided into different classes, with each class characterized by a biological function and a reduction potential. Site-specific mutagenesis of the sequence determinants of the differences in the reduction potential between classes should change the reduction potential of a protein in one class to that of the other class. Here, a procedure is presented that combines energetic and bioinformatic analysis of homologous proteins to identify sequence determinants that are also good candidates for site-specific mutations, using the [4Fe–4S] ferredoxins and the [4Fe–4S] high-potential iron–sulfur proteins as examples. This procedure is designed to guide site-specific mutations or more computationally expensive studies, such as molecular dynamics simulations. To make the procedure more accessible to the general scientific community, it is being implemented into CHARMMing, a Web-based portal, with a library of density functional theory results for the redox site that are used in the setting up of Poisson–Boltzmann continuum electrostatics calculations for the protein energetics.

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Acknowledgments

This work was supported by a grant from the National Institutes of Health (GM0453030) and by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute in the Laboratory of Computational Biology (Z99-TW999999-03). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the US Government. The continuum electrostatic calculations were performed using computers funded through the William G. McGowan Foundation and Georgetown University. Both authors thank Kelly N. Tran and Mingliang Tan for careful reading of the manuscript.

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  1. Department of Chemistry, Georgetown University, Box 571227, Washington, DC, 20057-1227, USA

    Bradley Scott Perrin Jr. & Toshiko Ichiye

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  1. Bradley Scott Perrin Jr.
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  2. Toshiko Ichiye
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Correspondence to Toshiko Ichiye.

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Perrin, B.S., Ichiye, T. Identifying sequence determinants of reduction potentials of metalloproteins. J Biol Inorg Chem 18, 599–608 (2013). https://doi.org/10.1007/s00775-013-1004-6

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