Structural, Thermodynamic, and Dynamic Descriptors for Differential Mechanism of HIF-2 Activity Modulators

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors critical for cellular adaptation to low oxygen conditions. Both enhancement and inhibition of HIF-2 activity has been shown to have a significant therapeutic relevance. We used all atom molecular dynamics (MD) simulations to elucidate the molecular mechanism for the differential effects of HIF-2 ligands on its complex with aryl hydrocarbon receptor nuclear translocator (ARNT). We find that agonists and antagonists differentially alter the binding site conformation, enthalpically strengthening or weakening the heterodimerization, respectively. These local changes were linked to conformational fluctuations of the HIF-2/ARNT complex, adding an entropic component to the effect of ligand binding on stability. Finally, we report a ligand-dependent effect on the DNA-binding bHLH domain’s structure and dynamics, impacting the hypoxia response element (HRE) binding. Based on these findings, we present a multiscale approach to enable high-throughput virtual screening of ligands for differential modulation of the structure, dynamics, and transcriptional activity of the HIF-2/ARNT complex.