Fe(II)/Fe(III) Redox Process Can Significantly Modulate the Conformational Dynamics and Electrostatics of Pirin in NF-κB Regulation

Pirin is an iron (Fe)-dependent regulatory protein of nuclear factor κB (NF-κB) transcription factors. Binding studies have suggested that the oxidative state of iron plays a crucial role in modulating the binding of Pirin to NF-κB p65, in turn enhancing the binding of p65 to DNA. The Fe­(III) form of Pirin is the active form and binds to NF-κB, whereas the Fe­(II) form does not bind to NF-κB. However, the surprising consequence of a single charge perturbation in the functional modulation of NF-κB is not well understood. Here, we use quantum mechanical calculations and microsecond-long molecular dynamics simulations to explore the free-energy landscapes of the Fe­(II) and Fe­(III) forms of Pirin. We show that the restricted conformational space and electrostatic complementarity of the Fe­(III) form of Pirin are crucial for binding and regulation of NF-κB. Our results suggest that a subtle single-electron redox trigger could significantly modulate the conformational dynamics and electrostatics of proteins in subcellular allosteric regulatory processes.