Molecular modeling revealed that ligand dissociation from thyroid hormone receptors is affected by receptor heterodimerization.

Numerous ligands bind tightly to thyroid hormone receptors (TRs), and exploring the binding and dissociation of these ligands from TRs will increase our understanding of their mechanisms of action. TRs form transcriptionally active heterodimers with retinoid X receptor (RXR); whether this heterodimerization affects ligand dissociation is poorly understood. To investigate the effects of heterodimerization, classical molecular dynamics (MD) simulations and random acceleration molecular dynamics (RAMD) simulations were performed to probe the dissociation of triiodothyronine (T3) from a TRα-RXR ligand binding domain (LBD) heterodimer and the TRα and TRβ LBDs at the atomic level. Seven (I-VII) dissociation pathways were identified for T3. Heterodimerization inhibited pathway I in the TRα-RXR LBD heterodimer, which may block the proper orientation of the helix 12 (H12), therefore affecting the biological functions of TRs. Upon TR heterodimerization, the second most dominant dissociation pathway switched from pathway IV for TRα LBD to pathway II for TRα-RXR LBD. No significant effects of TR heterodimerization were observed on the dominant dissociation pathway III that was located between H3, the H1-H2 loop and the β-sheet. Our study revealed that TR heterodimerization significantly affects T3 dissociation, which provides important information for the study of other TR ligands.