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 anticooperative 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 theNAMD. 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.

基于配体的变构物因其在蛋白质调节和药物设计中的重要性而受到关注。蛋白质变构的有趣例子之一是甲状腺激素受体-类维生素A x受体（TR：RXR），它调节重要生理过程（例如发育和代谢）的基因表达。它受TR天然配体三碘甲腺氨酸（T3）的调控，它对RXR配体9-顺式视黄酸（9C）表现出抗合作性。与这种抗合作行为相反，已证明9C可增加TR：RXR的活性。在这里，我们通过接触动力学和残基网络探究了TR配体对TR：RXR的构象的亲和力和相互作用的影响。当与TR：RXR（9C）复合物对接时，TR配体类似物被设计为具有比T3高的（G2）和较低的（N1）结合能。使用NAMD对TR（N1 / T3 / G2）：RXR（9C）水溶液进行30 ns全原子模拟。CAMERRA程序用于通过映射残留物接触动力学来捕获TR：RXR的细微扰动。TR配体的各个部分；包括亲水头，碘取代基和配体尾；已经探究了它们在配体亲和力中的重要性。T3和G2复合物的结果表明，配体亲和力可以用作抗合作系统的预测因子，在该系统上，配体更可能解离或保持结合。所有这三种复合物还显示出不同的接触网络，用于跨二聚体信号传导和配体通信。