Molecular dynamics investigation of stereoselective inhibition mechanism of HIF-2α/ARNT heterodimer.
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors related with the onset and progression of solid tumors. Studies demonstrated a class of tetrazole containing chiral inhibitors could stereoselectively disrupt the HIF-2 dimerization and reduce the target gene expression. However, the dynamical features and structural motifs of the HIF-2 heterodimer caused by the binding of enantiomers have not been rationalized at the atomistic level. In this work, molecular dynamics (MD) simulations combined with adaptive steered MD (ASMD) simulations were used to investigate stereoselective interrupting mechanism of HIF-2. Our results decipher that the binding of ligand A (S, R)-24 begets the significant conformation changes of β-sheets and interrupts the HIF-2α/ARNT heterodimerization, which may be attributed to the disruption of the hydrogen bond and salt bridge interactions formed by the 4 foremost residues (Asp240, Arg247, Glu362, and Arg366) and the destruction of hydrophobic interactions on the binding interface. By contrast, the binding of ligand B (R, S)-24 does not disrupt protein dimerization and causes the motion of Fα helix in HIF-2α PAS-B domain to further change the major tunnel for ligand ingress and engress. The present work provides important molecular-level insight into the effect of the binding enantiomers on HIF-2 heterodimerization and bridges the gap between theory and the experimental results, which may conduce to develop highly potent antagonists for intervening the HIF-2-driven tumors.
['Sun|Dong-Ru|DR|', 'Zheng|Qing-Chuan|QC|0000-0003-2978-768X', 'Zhang|Hong-Xing|HX|']
D020816:Amino Acid Motifs D051784:Aryl Hydrocarbon Receptor Nuclear Translocator D051792:Basic Helix-Loop-Helix Transcription Factors D019281:Dimerization D006801:Humans D006860:Hydrogen Bonding D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D011485:Protein Binding D054730:Protein Interaction Domains and Motifs D013237:Stereoisomerism D013816:Thermodynamics
disruption HIF-2 heterodimer MM-GBSA molecular dynamics simulation