Molecular dynamics investigation of stereoselective inhibition mechanism of HIF‐2α/ARNT heterodimer

Abstract

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.

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

“…The lessened contacts of interdomain forcefully indicate that some crucial interactions between HIF‐2α and ARNT are disrupted as binding of 2 inhibitors. Our previous study has shown that the apo 1 was stabilized by the foremost H‐bond and salt bridge interactions (Asp240‐Arg366 and Arg247‐Glu362) as well as the assistant H‐bonds (Tyr327‐Arg440 and Glu320‐Tyr450) located on the β‐sheets of binding interface. When the PT2399 and 0X3 bind into the HIF‐2α domain, these foremost H‐bond and salt bridge interactions (Asp240‐Arg366 and Arg247‐Glu362) are largely disrupted, and the assistant H‐bonds (Tyr327‐Arg440 and Glu320‐Tyr450) are still retained (Figure D‐F, Table , and Table S3).…”

Implementation of Telescoping Boxes in Adaptive Steered Molecular Dynamics

“…As many applications − of the external force involve the restructuring of the target system, the solvent box is often large and exacerbates the cost of the sampling. Beyond our group, ASMD has been used successfully to obtain the energetics of several challenging systems, including the characterization of a host–guest interaction, , mechanism of the complex dynamics, mutagenesis, binding affinity, protein–ligand interactions, − and protonation effects …”