PNNL

The Science

[4Fe-4S] clusters sit at the core of important enzymes, playing central roles in energy metabolism and other biological processes. The reduction potential of these clusters can be tuned over a wide energy range by the hosting protein environment. A theoretical study probed how charge distribution and structural alterations affected the electronics of the [4Fe-4S] clusters. Directionally biased electrostatic interactions are the key to tuning the reduction potential of [4Fe-4S] clusters over 1V, while geometrical distortion accounts for changes in a 100 mV range.

The Impact

[4Fe-4S] clusters are essential for catalysis and electron transfer in all life forms and have reduction potentials that are finely tuned by the surrounding environment. Identifying how specific aspects of the environment alter the cluster reduction potential can help researchers design more effective catalysts with specific electronic properties. This study provides a systematic theoretical analysis linking charge distribution and structural distortion to redox variability in the clusters. The new insights can lead to design principles for bioinspired catalysts targeted at a range of energy transfer reactions.

Summary

[4Fe-4S] clusters are ubiquitous in living systems and crucial to energy metabolism, serving as intermediates in inter- and intramolecular electron transfer pathways. The clusters can adopt a surprisingly wide range of reduction potentials spanning more than 1 V. The characteristics of the environment, including charge, solvent access, and geometric distortion, modulate the reduction potential of iron/sulfur clusters to a fine degree; however, prior research has not systematically probed cause and effect. In this work, researchers conducted a thorough theoretical assessment of how charge distribution and structural distortion contribute to the full range of reduction potentials exhibited by biological [4Fe-4S] clusters. While geometric distortions influence the potential, their effects are modest. The more significant contributions can be attributed to electrostatic interactions, which are directionally biased. The electrostatic effects are most pronounced when the charge is closest to the cubane sulfides versus the cysteinyl thiolates. The calculations showed a linear relationship between charge magnitude and ionization potential. The observed range of redox potentials was accompanied by notable differences in the iron coupling constants, indicating that the overall tuning of reduction potentials is caused by sulfides-focused electrostatic interactions.

Contact

Simone Raugei, Pacific Northwest National Laboratory, simone.raugei@pnnl.gov 

Funding

Funding was provided by the Department of Energy (DOE), Office of Science (SC), Basic Energy Sciences (BES), Materials Sciences and Engineering Division, Biomolecular Materials Program, under FWP77876 (B.D. and M.D.B. for the normal mode analysis), the DOE/BES Chemical Sciences, Geosciences, and Biosciences Division, Physical Biosciences Program, under FWP 66476 (B.D., M.D.B., and S.R. for the electrostatic analysis), and the National Institutes of Health under grant 1R01GM1385920 (J.W.P. and S.R.). Computational resources were provided by the Molecular Sciences Computing Facility in the Environmental Molecular Sciences Laboratory, a DOE user facility located at the Pacific Northwest National Laboratory (PNNL), and the National Energy Research Scientific Computing Center, supported by the DOE SC.