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

In: Journal of Chemical Theory and Computation, Vol. 11, No. 8, 11.08.2015, p. 3946-3954.

Research output: Contribution to journalArticle

Harvard

Domene, C, Jorgensen, C, Vanommeslaeghe, K, Schofield, CJ & MacKerell, A 2015, 'Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor', Journal of Chemical Theory and Computation, vol. 11, no. 8, pp. 3946-3954. https://doi.org/10.1021/acs.jctc.5b00411

APA

Domene, C., Jorgensen, C., Vanommeslaeghe, K., Schofield, C. J., & MacKerell, A. (2015). Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor. Journal of Chemical Theory and Computation, 11(8), 3946-3954. https://doi.org/10.1021/acs.jctc.5b00411

Vancouver

Domene C, Jorgensen C, Vanommeslaeghe K, Schofield CJ, MacKerell A. Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor. Journal of Chemical Theory and Computation. 2015 Aug 11;11(8):3946-3954. https://doi.org/10.1021/acs.jctc.5b00411

Author

Domene, Carmen ; Jorgensen, Christian ; Vanommeslaeghe, Kenno ; Schofield, Christopher J ; MacKerell, Alexander. / Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor. In: Journal of Chemical Theory and Computation. 2015 ; Vol. 11, No. 8. pp. 3946-3954.

Bibtex Download

@article{329af7b42d884008adee7c8281ab78ca,
title = "Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor",
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.",
keywords = "FREE-ENERGY CALCULATIONS, MOLECULAR-DYNAMICS, PROLYL HYDROXYLATION, FORCE-FIELDS, HIF, PROTEIN, HIF-1-ALPHA, PVHL, HYDROXYPROLINE, RECOGNITION",
author = "Carmen Domene and Christian Jorgensen and Kenno Vanommeslaeghe and Schofield, {Christopher J} and Alexander MacKerell",
year = "2015",
month = aug,
day = "11",
doi = "10.1021/acs.jctc.5b00411",
language = "English",
volume = "11",
pages = "3946--3954",
journal = "Journal of Chemical Theory and Computation",
issn = "1549-9618",
publisher = "American Chemical Society",
number = "8",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor

AU - Domene, Carmen

AU - Jorgensen, Christian

AU - Vanommeslaeghe, Kenno

AU - Schofield, Christopher J

AU - MacKerell, Alexander

PY - 2015/8/11

Y1 - 2015/8/11

N2 - 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.

AB - 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.

KW - FREE-ENERGY CALCULATIONS

KW - MOLECULAR-DYNAMICS

KW - PROLYL HYDROXYLATION

KW - FORCE-FIELDS

KW - HIF

KW - PROTEIN

KW - HIF-1-ALPHA

KW - PVHL

KW - HYDROXYPROLINE

KW - RECOGNITION

U2 - 10.1021/acs.jctc.5b00411

DO - 10.1021/acs.jctc.5b00411

M3 - Article

C2 - 26574473

VL - 11

SP - 3946

EP - 3954

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

SN - 1549-9618

IS - 8

ER -

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