Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel–Lindau Suppressor

• DOI: 10.1021/acs.jctc.5b00411
• Publication Date: 2015-06-29T17:21:58Z
• Authors: Carmen Domene; Christian Jorgensen; Kenno Vanommeslaeghe; Christopher J. Sc...; Alexander MacKerell
• Keywords: Hydroxylation; Hydroxyproline; Hypoxia; Transcription; Hypoxia-Inducible Factor 1

The hypoxia-inducible transcription factors (HIF) play a central role in the human oxygen sensing signaling pathway. binding of von Hippel–Lindau tumor suppressor protein (pVHL)–ElonginC–ElonginB complex (VCB) to HIF-1α is highly selective for trans-4-hydroxylation form when Pro564 C-terminal oxygen-dependent degradation domain (ODDD) HIF-1α. HIFα VCB increased by ∼1000-fold upon addition single hydroxyl group either two conserved proline-residues. Here, we address how this governs recognition and characterizes strength interaction “switch-like” event. A new set molecular mechanics parameters 4-hydroxyproline has been developed following CHARMM force field philosophy. Using free energy perturbation (FEP) formalism, difference energies between nonhydroxylated hydroxylated forms with was estimated using over 3 μs MD trajectories. These results can favorably be compared an experimental value ∼4 kcal mol–1. It observed that optimized hydrogen bonding network buried hydroxyprolyl confers precise discrimination unmodified prolyl residues. observations provide insight will aid developing therapeutic agents block HIF-α pVHL.