Enhanced Sampling Applied to Modeling Allosteric Regulation in Transcription.

Allosteric regulation by intrinsically disordered proteins (IDPs) is an important class of cellular processes, including transcription. Molecular dynamics (MD) simulation is a promising approach to unravel the complex molecular interactions involved in the allosteric regulation by IDPs. While allosteric regulation is often characterized by the effect of a ligand on the binding affinity of a distal ligand, the binding affinity is often challenging to calculate by MD simulations because of insufficient sampling of the rare events in this binding-unbinding process. In the current work, we present a new sampling approach based on Hamiltonian replica exchange that allows accurate and efficient calculation of binding affinities using a native-centric coarse-grained model. We also demonstrate the utility of the new method by studying the positive allostery in the kinase-inducible domain interacting domain of the CREB binding protein, in which a prebound ligand enhances the binding of the second ligand.