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Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel–Lindau Suppressor
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    Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel–Lindau Suppressor
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    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn St., Baltimore, Maryland 21201, United States
    Physical & Theoretical Chemistry Laboratory, South Parks Road, University of Oxford, Oxford OX1 3QZ, United Kingdom
    § Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom
    *Telephone: +44-1865 285110. E-mail: [email protected]
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    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2015, 11, 8, 3946–3954
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    https://doi.org/10.1021/acs.jctc.5b00411
    Published June 29, 2015
    Copyright © 2015 American Chemical Society

    Abstract

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    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.

    Copyright © 2015 American Chemical Society

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    Supporting Information

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    Tables with hydroxyproline force field parameters and topology; scaled ab initio and MM vibrational spectra of cis- and trans-hydroxyproline; average RMSD values and standard deviation for the peptide in solution and the enzyme complexes; key H-bond differences between clusters of pVHL:HIF-1α(Hyp564) and pVHL:HIF-1α(Pro564); snapshots indicating distances between HIF-1α:Pro564(H) to S111(O) and H115(N), and HIF-1α-Hyp564(O)-S111(H) and HIF-1α-Hyp564(H)-H115(N); free energy profile for an Enz-Hyp simulation with different scaling parameters; effect of window number in ΔG for the Enz-Hyp transformation; free energy profile for the Pep-Pro state considering simulations with different lengths; and free energy of binding as the difference between the free energy of the transformation of Pro564 to Hyp564 in the peptide (Pep-Pro) and enzyme (Enz-Pro) states. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jctc.5b00411.

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    Cited By

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    This article is cited by 1 publications.

    1. Martine I. Abboud, Tom E. McAllister, Ivanhoe K. H. Leung, Rasheduzzaman Chowdhury, Christian Jorgensen, Carmen Domene, Jasmin Mecinović, Kerstin Lippl, Rebecca L. Hancock, Richard J. Hopkinson, Akane Kawamura, Timothy D. W. Claridge, Christopher J. Schofield. 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2. Chemical Communications 2018, 54 (25) , 3130-3133. https://doi.org/10.1039/C8CC00387D

    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2015, 11, 8, 3946–3954
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jctc.5b00411
    Published June 29, 2015
    Copyright © 2015 American Chemical Society

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