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Unfolding mechanism of PHD2 as a vital protein: all-atom simulation approach

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Abstract

Prolyl hydroxylase domain 2 containing protein (PHD2) is a central protein in regulation of cellular response to hypoxia. This protein controls the responses of cell to oxygen level via the regulation of hypoxia inducible factor (HIF) stability. HIF induces the expression of many genes, especially ones orchestrate angiogenesis. There are some reports that mentioned in some tumor types the level of HIF is high in spite of the presence of wild-type PHD2 and normoxic environment. Therefore, the possibility of PHD2 misfolding in some cancer cells arises. Studying such important protein unfolding pathway is insightful for possible therapeutic approaches. In this study, the unfolding pathway of PHD2 illustrates utilizing molecular dynamics simulation of protein thermal denaturation. Based on current study results, we represent the possible mechanisms of PHD2 unfolding in detail. The possible intermediates of PHD2 thermal unfolding are characterized, and the most venomous state of its unfolding pathway is introduced.

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Acknowledgments

We gratefully acknowledge the support of the University of Tehran, Iran National Science Foundation (INSF), and the Center of Excellence in Biothermodynamics (CEBiotherm).

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Authors and Affiliations

  1. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Hamid Hadi-Alijanvand, Ali A. Moosavi-Movahedi & Bahram Goliaei

  2. Department of Biological Science, Institute for Advanced Studies in Basic Sciences, Zanjan, Iran

    Hamid Hadi-Alijanvand

  3. Center of Excellence in Biothermodynamics, IBB, University of Tehran, Tehran, Iran

    Ali A. Moosavi-Movahedi

Authors
  1. Hamid Hadi-Alijanvand
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  2. Ali A. Moosavi-Movahedi
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  3. Bahram Goliaei
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Correspondence to Ali A. Moosavi-Movahedi.

Electronic supplementary material

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13738_2013_227_MOESM1_ESM.tif

SI-1 To have estimation about the correspondence of PHD2 3D structure and 2D map of X, Y coordinates of PHD2 Cα along 25-ns MD, this graph is generated. Equal regions of 2D map and 3D structure are clarified via arrows. Darker regions are more populated. (TIF 1.48 mb)

13738_2013_227_MOESM2_ESM.gif

SI-2 This animated image shows the distribution of Cl+ ions in simulation space around PHD2 protein along 25-ns MD. PHD2 is represented by ribbon structure. Cl+ ions are presented via color points. Each color of point represents a specific ion with unique atom ID. As this animation demonstrates, a very small fraction of Cl+ atoms penetrated to PHD2 core. (GIF 3.91 mb)

13738_2013_227_MOESM3_ESM.gif

SI-3 This animated image shows the distribution of Na+ ions in simulation space around PHD2 protein along 25-ns MD. PHD2 is represented by ribbon structure. Na+ ions are presented via color points. Each color of point represents a specific ion with unique atom ID. As this animation demonstrates, substantial fraction of Na+ atoms penetrated to PHD2 core. (GIF 7.04 mb)

13738_2013_227_MOESM4_ESM.tif

SI-4 The APBS computed electrostatic potential (EP) of PHD2 is represented. Red surface stands for regions with negative EP. Regions with positive EP are highlighted by blue surface. (TIF 680 kb)

13738_2013_227_MOESM5_ESM.gif

SI-5 The negative electrostatic potential of PHD2 is represented via EP filed lines. This animated image shows that negative EP penetrates into PHD2 lumen, and therefore, such EP attracts positive ions to protein core. (GIF 3.73 mb)

13738_2013_227_MOESM6_ESM.tif

SI-6 This graph represents the interaction energy between ion and PHD2 residue’s types along 25-ns simulation time. Panel (a) shows interaction energies smaller than −0.5 kcal/mol. The (b) and (c) sections represent interaction energies smaller than 1.0 and 2.0 kcal/mol, respectively. The most strong attraction energies between ions and residues present in panel (c). (TIF 1.15 mb)

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Hadi-Alijanvand, H., Moosavi-Movahedi, A.A. & Goliaei, B. Unfolding mechanism of PHD2 as a vital protein: all-atom simulation approach. J IRAN CHEM SOC 10, 907–914 (2013). https://doi.org/10.1007/s13738-013-0227-3

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  • DOI: https://doi.org/10.1007/s13738-013-0227-3

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