Electron transfer between proteins is mediated by transient complexes that sample many binding orientations, only a subset productive. Protein electron carriers (PECs) form such complexes with diverse enzymes across central metabolism, yet no general framework predicts which PEC-enzyme pairs will function. A representative case is IspG, the iron-sulfur enzyme catalyzing the penultimate methylerythritol phosphate pathway reaction, whose [4Fe-4S] cluster must be reduced after each turnover by the Escherichia coli flavodoxin FldA. It is not known whether FldA engages the open (substrate-free) or closed (substrate-bound) conformation of IspG, or how the cofactor redox states shape their interaction. Using atomistic molecular dynamics with custom cofactor parameters, we find that FldA preferentially engages the open conformation, implying that reduction precedes substrate binding. A positively charged arginine patch anchors FldA, and a single residue, Tyr58, provides a short tunneling bridge to the cluster. Electron transfer then weakens this interface, driving the complex toward dissociation -- pointing to an intrinsic mechanism by which a PEC binds its targets transiently yet productively: conformational selection recruits the partner, and electron transfer releases it.
Loonen, S., Widjaja, S. Q., Bokinsky, G., Sostaric, N.
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