Molecular Dynamics Simulations of Ligand Dissociation from Thyroid Hormone Receptors: Evidence of the Likeliest Escape Pathway and Its Implications for the Design of Novel Ligands

Abstract

Steered molecular dynamics simulations of ligand dissociation from Thyroid hormone receptors indicate that dissociation is favored via rearrangements in a mobile part of the LBD comprising H3, the loop between H1 and H2, and nearby β-sheets, contrary to current models in which the H12 is mostly involved. Dissociation is facilitated in this path by the interaction of the hydrophilic part of the ligand with external water molecules, suggesting strategies to enhance ligand binding affinity.