posted on 2021-04-05, 06:29authored bySoundhararajan Gopi, Bincy Lukose, Athi N. Naganathan
Native states of folded proteins are characterized by a large ensemble
of conformations whose relative populations and interconversion dynamics
determine the functional output. This is more apparent in transcription
factors that have evolved to be inherently sensitive to small perturbations,
thus fine-tuning gene expression. To explore the extent to which such
functional features are imprinted on the folding landscape of transcription
factor ligand-binding domains (LBDs), we characterize paralogous LBDs
of the nuclear receptor (NR) family employing an energetically detailed
and ensemble-based Ising-like statistical mechanical model. We find
that the native ensembles of the LBDs from glucocorticoid receptor,
PPAγ, and thyroid hormone receptor display a remarkable diversity
in the width of the native wells, the number and nature of partially
structured states, and hence the degree of conformational order. Monte
Carlo simulations employing the full state representation of the ensemble
highlight that many of the functional conformations coexist in equilibrium,
whose relative populations are sensitive to both temperature and the
strength of ligand binding. Allosteric modulation of the degree of
structure at a coregulator binding site on ligand binding is shown
to arise via a redistribution of populations in the native ensembles
of glucocorticoid and PPAγ LBDs. Our results illustrate how
functional requirements can drive the evolution of conformationally
diverse native ensembles in paralogs.