Charge Transfer between [4Fe4S] Proteins and DNA Is Unidirectional: Implications for Biomolecular Signaling

We investigate the role of DNA mediation in redox signaling processes between [4Fe4S] clusters that are relevant to DNA replication and repair. Through kinetic modeling, electronic structure calculations, and thermodynamic analysis, our theoretical study demonstrates that charge transfer between a [4Fe4S] cluster and a nucleic acid duplex bound to the [4Fe4S] protein is unidirectional. This unidirectionality implies that the DNA mediation of biological redox signaling needs to be assisted by charge injection into the duplex from cellular oxidants or reductants. Using this important mechanistic implication and the dependence of DNA binding affinity on the charging state of the [4Fe4S] cluster, we identify a set of possible mechanisms, based on charge transfer, for redox signaling between high-potential [4Fe4S] proteins involved in DNA replication and repair. Our analysis of these signaling mechanisms fosters experimental studies of functional charge transfer in [4Fe4S] protein systems.