Molecular Dynamics Simulations Reveal Multiple Pathways of Ligand Dissociation from Thyroid Hormone Receptors

¹ Instituto de Química, UNICAMP
² Diabetes Center and Metabolic Research Unit, University of California, San Francisco
³ Instituto de Física de São Carlos, Universidade de São Paulo

^* To whom correspondence should be addressed. E-mail: ipolikarpov{at}if.sc.usp.br.

Submitted on March 30, 2005
Revised on May 5, 2005
Accepted on 9 June 2005

	Abstract

Nuclear Receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understood. Here, we utilize Enhanced Sampling Molecular Dynamics computer simulations to predict molecular motions in X-ray structures of thyroid hormone receptor (TR) LBDs and determine events that permit ligand escape. We find that the natural ligand 3,5,3'-triiodo-L-thyronine (T3) dissociates from the TRa1 LBD along three competing pathways generated through: I) Opening of helix (H) 12; II) Separation of H8 and H11 and the W-loop between H2 and H3; III) Opening of H2 and H3, and the intervening b-strand. Similar pathways are involved in dissociation of T3 and the TRb selective ligand GC24 from TRb; the TR agonist IH5 from the á- and â-TR forms; and Triac from two natural human TRb mutants, A317T and A234T, but are detected with different frequencies in simulations performed with the different structures. Whereas Path I was previously suggested to represent a major pathway for NR ligand dissociation, we propose that Paths II and III are also likely ligand escape routes for TRs and other NRs. We also propose that different escape paths are preferred in different situations, implying that it will be possible to design NR ligands that only associate stably with their cognate receptors in specific cellular contexts.

Key Words: ligand dissociation, molecular dynamics, nuclear receptors, thyroid hormone receptor

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