Effect of Oriented Electric Fields on Biologically Relevant Iron-Sulfur Clusters: Tuning Redox Reactivity for Catalysis.

Samuel J H Gaughan,Anna K Croft,Christof M Jäger,Jonathan D Hirst

doi:10.1021/acs.jcim.1c00791

Samuel J H Gaughan, Anna K Croft + Show 2 more

Open Access

https://doi.org/10.1021/acs.jcim.1c00791

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Abstract

Enzyme-based iron-sulfur clusters, exemplified in families such as hydrogenases, nitrogenases, and radical S-adenosylmethionine enzymes, feature in many essential biological processes. The functionality of biological iron-sulfur clusters extends beyond simple electron transfer, relying primarily on the redox activity of the clusters, with a remarkable diversity for different enzymes. The active-site structure and the electrostatic environment in which the cluster resides direct this redox reactivity. Oriented electric fields in enzymatic active sites can be significantly strong, and understanding the extent of their effect on iron-sulfur cluster reactivity can inform first steps toward rationally engineering their reactivity. An extensive systematic density functional theory-based screening approach using OPBE/TZP has afforded a simple electric field-effect representation. The results demonstrate that the orientation of an external electric field of strength 28.8 MV cm-1 at the center of the cluster can have a significant effect on its relative stability in the order of 35 kJ mol-1. This shows clear implications for the reactivity of iron-sulfur clusters in enzymes. The results also demonstrate that the orientation of the electric field can alter the most stable broken-symmetry state, which further has implications on the directionality of initiated electron-transfer reactions. These insights open the path for manipulating the enzymatic redox reactivity of iron-sulfur cluster-containing enzymes by rationally engineering oriented electric fields within the enzymes.

Highlights

Iron−sulfur clusters play a critical role in reactions catalyzed by several families of enzymes, providing a wide variety of functions in each
Radical S-adenosylmethionine enzymes make use of a [4Fe4S] cluster to reductively cleave S-adenosylmethionine (SAM) into methionine and the 5′-deoxyadenosyl radical, the latter of which is used to initiate a variety of radical reactions that have been reviewed previously.[10−13] In some cases, electron transfer may be an intermediate step rather than the complete function of an enzyme, such as the case of the biotin synthase radical S-adenosylmethionine (rSAM) mechanism in which the FeS clusters mediate the donation of a sulfur atom.[14]
The methods used by other groups include B(5%HF)P86 and a triple-ζ basis set with polarization functions for accurate bond covalency[65,66] and B(5%HF)P86/ 6-311+G(d) for the quantum mechanics (QM) region of a QM/molecular mechanics (MM) study into the protein environmental effects around the iron−sulfur clusters.[67]

Summary

Introduction

Iron−sulfur clusters play a critical role in reactions catalyzed by several families of enzymes, providing a wide variety of functions in each. Their possible role in enabling the emergence of early life[1] and capacity to perform many different roles within enzymatic pathways[2,3] has led to them being characterized as “one of the most ubiquitous and functionally versatile prosthetic groups in nature”.4. Radical S-adenosylmethionine (rSAM) enzymes make use of a [4Fe4S] cluster to reductively cleave S-adenosylmethionine (SAM) into methionine and the 5′-deoxyadenosyl radical, the latter of which is used to initiate a variety of radical reactions that have been reviewed previously.[10−13] In some cases, electron transfer may be an intermediate step rather than the complete function of an enzyme, such as the case of the biotin synthase rSAM mechanism in which the FeS clusters mediate the donation of a sulfur atom.[14]

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Conclusion