Molecular Dynamics Simulations Reveal the Importance of Non-Native Interactions in Modulating the Inactive to Active Conformational Transition in Progesterone Receptor

Nuclear receptors are a family of transcription factors that activate respective genes when bound to specific ligands. Certain ligands induce conformational changes in the receptor which helps them recruit co-activators. The conformational changes induced by these ligands conformationally transition inactive conformation into an active conformation by changing the orientation of the C-terminal helix (H12). Despite their immense physiological importance, very few questions have been solved about the kinetics and the molecular mechanism of this transition from the inactive to active conformation. In this study, we have used extensive unbiased atomistic molecular dynamics simulations of Progesterone receptor bound to a partial agonist asoprisnil to investigate these two questions. Two different crystal structures for this complex provide us with a unique opportunity to study the conformational transition at the molecular level. Apart from elucidating several important dynamical information from these simulations, we used Markov state modeling to calculate the rate of the transition between the inactive and active-like states. More importantly, we have also shown the importance of non-native interactions in this conformational transition, which were seen to be formed during the transition from inactive to active-like conformation but not present in the active conformation itself. Apart from contributing to our fundamental understanding about the structure and dynamics of nuclear receptor at the molecular level, this study might be able to contribute to the larger problem of protein-folding itself.