Molecular stripping in the NFκB/IκB/DNA genetic regulatory network

Abstract

Genetic switches based on the NF{kappa}B/I{kappa}B/DNA system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that I{kappa}B can actively remove NF{kappa}B bound to its genetic sites via a process called \"molecular stripping\". This allows the NF{kappa}B/I{kappa}B/DNA switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor NF{kappa}B and its various binary and ternary complexes with DNA and the inhibitor I{kappa}B. These studies show that the function of the NF{kappa}B/I{kappa}B/DNA genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of I{kappa}B which occurs through conformational selection. Free energy calculations for DNA binding show that the binding of I{kappa}B not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.