Virtual Model Compound Approach for Calculating Redox Potentials of [Fe₂S₂]-Cys₄ Centers in Proteins – Structure Quality Matters

Title data

Roy, Rajeev Ranjan ; Ullmann, G. Matthias:
Virtual Model Compound Approach for Calculating Redox Potentials of [Fe₂S₂]-Cys₄ Centers in Proteins – Structure Quality Matters.
In: Journal of Chemical Theory and Computation. Vol. 19 (2023) Issue 23 . - pp. 8930-8941.
ISSN 1549-9626
DOI: https://doi.org/10.1021/acs.jctc.3c00779

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Abstract in another language

The midpoint potential of the [Fe2S2]-Cys4-cluster in proteins is known to vary between −200 and −450 mV. This variation is caused by the different electrostatic environment of the cluster in the respective proteins. Continuum electrostatics can quantify the impact of the protein environment on the redox potential. Thus, if the redox potential of a [Fe2S2]-Cys4-cluster model compound in aqueous solution would be known, then redox potentials in various protein complexes could be calculated. However, [Fe2S2]-Cys4-cluster models are not water-soluble, and thus, their redox potential can not be measured in aqueous solution. To overcome this problem, we introduce a method that we call Virtual Model Compound Approach (VMCA) to extrapolate the model redox potential from known redox potentials of proteins. We carefully selected high-resolution structures for our analysis and divide them into a fit set, for fitting the model redox potential, and an independent test set, to check the validity of the model redox potential. However, from our analysis, we realized that the some structures can not be used as downloaded from the PDB but had to be re-refined in order to calculate reliable redox potentials. Because of the re-refinement, we were able to significantly reduce the standard deviation of our derived model redox potential for the [Fe2S2]-Cys4-cluster from 31 mV to 10 mV. As the model redox potential, we obtained −184 mV. This model redox potential can be used to analyze the redox behavior of [Fe2S2]-Cys4-clusters in larger protein complexes.