Nuclear receptors regulate transcriptional programs in response to the binding of natural and synthetic ligands. These ligands modulate the receptor by inducing dynamic changes in the ligand binding domain that shift the C-terminal helix (H12) between active and inactive conformations. Despite decades of study, many questions persist regarding the nature of the inactive state and how ligands shift receptors between different states. Here, we use molecular dynamics (MD) simulations to investigate the timescale and energetic landscape of the conformational transition between inactive and active forms of progesterone receptor (PR) bound to a partial agonist. We observe that the microsecond timescale is insufficient to observe any transitions; only at millisecond timescales achieved via accelerated MD simulations do we find the inactive PR switches to the active state. Energetic analysis reveals that both active and inactive PR states represent energy minima separated by a barrier that can be traversed. In contrast, little or no transition is observed between active and inactive states when an agonist or antagonist is bound, confirming that ligand identity plays a key role in defining the energy landscape of nuclear receptor conformations.
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