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.