Electron Transfer and Assembly in Fe-S Proteins
Perrin Jr., Bradley S.
The iron-sulfur (Fe-S) proteins are a major class of metalloproteins, with metal sites consisting of varying numbers of iron and sulfur atoms. Most Fe-S proteins are electron transfer proteins involved in processes such as respiration, photosynthesis, and nitrogen fixation. The reduction potentials of these proteins determine the driving forces for their electron transfer. For a given redox site, reduction potentials of non-homologous proteins can span a range of ~1 V, while those of homologous proteins can span a range of ~400 V. Here, a method for calculating the reduction potentials of metalloproteins is presented in which the redox site or inner sphere contribution is calculated by density functional theory (DFT) and the protein or outer sphere contribution is calculated by Poisson-Boltzmann (PB) continuum electrostatics. Reduction potentials calculated using the DFT+PB method are in excellent agreement with the experimental values for several Fe-S proteins. Moreover, the calculations show that for the outer sphere, the protein fold makes the largest contribution while the sequence tunes it. Furthermore, they show that the fold contribution is determined mainly by the burial of the redox site within the protein and the polarization of the protein environment around the redox site. Based on this, an electret-dielectric spheres (EDS) model is developed in terms of R<sub>p</sub>, a measure of the redox site burial and <italic>φ</italic><sub>p</sub>, the electrostatic potential at the redox site. The DFT+PB method is also used to identify sequence determinants of reduction potentials, which can be tested by site-specific mutagenesis experiments.Finally, a new class of Fe-S proteins have recently been discovered that behave as scaffold proteins for the assembly of Fe-S clusters in proteins. However, although crystal structures of the primary scaffold, IscU, and a proposed secondary scaffold, IscA, have been solved, the mode of binding of Fe-S clusters to these proteins is still unclear. Molecular dynamics simulations of these proteins were performed to elucidate the binding. Based on the simulations, two cysteines in IscA are identified that could be involved in the initial binding of a cluster.
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