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

Research output: Contribution to journalArticle

Carmen Domene, Christian Jorgensen, Kenno Vanommeslaeghe, Christopher J Schofield, Alexander MacKerell

Original languageEnglish
Pages (from-to)3946-3954
Number of pages9
JournalJournal of Chemical Theory and Computation
Volume11
Issue number8
Early online date29 Jun 2015
DOIs
E-pub ahead of print29 Jun 2015
Published11 Aug 2015

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Abstract

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

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