The effect of ligand affinity to the contact dynamics of the ligand binding domain of thyroid hormone receptor - retinoid X receptor

Ligand-based allostery has been gaining attention for its importance in protein regulation and implication in drug design. One of the interesting cases of protein allostery is the thyroid hormone receptor - retinoid x receptor (TR:RXR), which regulates the gene expression of important physiological processes, such as development and metabolism. It is regulated by the TR native ligand triiodothyronine (T3), which displays anticooperative behavior to the RXR ligand 9-cis retinoic acid (9C). In contrast to this anti-cooperative behavior, 9C has been shown to increase the activity of TR:RXR. Here we probed the influence of the affinity and the interactions of the TR ligand to the allostery of the TR:RXR through contact dynamics and residue networks. The TR ligand analogs were designed to have higher (G2) and lower (N1) binding energies than T3 when docked to the TR:RXR(9C) complex. The aqueous TR(N1/T3/G2):RXR(9C) complexes were subjected to 30 ns all-atom simulations using the NAMD. The program CAMERRA was used to capture the subtle perturbations of TR:RXR by mapping the residue contact dynamics. Various parts of the TR ligands; including the hydrophilic head, the iodine substituents, and the ligand tail; have been probed for their significance in ligand affinity. The results on the T3 and G2 complexes suggest that ligand affinity can be utilized as a predictor for anticooperative systems on which ligand is more likely to dissociate or remain bound. All 3 complexes also display distinct contact networks for cross-dimer signalling and ligand communication. Understanding ligand-based allostery could potentially unveil secrets of ligand-regulated protein dynamics, a foundation for the design of better and more efficient allosteric drugs. (C) 2021 Elsevier Inc. All rights reserved.