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Magnesium interactions with a CX26 connexon in lipid bilayers

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Abstract

Following our previous work, where we described the interaction of calcium with the Cx26 hemichannel, we further explore the same system by atomistic molecular dynamics simulations considering a different di-cation, magnesium. Specifically, the interaction of magnesium di-cation with the previously reported calcium binding sites (ASP2, ASP117, ASP159, GLU114, GLU119, GLU120, and VAL226) was investigated to identify similarities and differences between them. In order to do so, four extensive simulations were carried out. Two of them considered a Cx26 hemichannel embedded on a POPC bilayer with one of the di-cations and a sodium-chlorine solution. For the remaining two, no di-cations were included and a sodium-chlorine or potassium-chlorine solution was considered. Potassium has a similar atomic mass to calcium, and sodium to magnesium, but they both differ in charge (1e and 2e respectively). Magnesium and calcium, even having the same charge, showed different affinity for the explored protein. From the calcium binding sites referred above, we found that the magnesium di-cations only binds strongly to the GLU114 site of one connexin. For the sodium and potassium simulations, no specific interactions with the protein were found. Altogether, these results suggest that mass and steric effects play an important role in determining cation binding to Cx26 hemichannels.

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References

  1. Trosko JE, Ruch RJ (1998) Cell-cell communication in carcinogenesis. Front Biosci 3:d208–d236. https://doi.org/10.2741/A275

    Article  CAS  PubMed  Google Scholar 

  2. Vinken MB, Vanhaecke T, Papeleu P et al (2006) Connexins and their channels in cell growth and cell death. Cell Signal 18:592–600. https://doi.org/10.1016/j.cellsig.2005.08.012

    Article  CAS  PubMed  Google Scholar 

  3. Vinken M (2015) Introduction: connexins, pannexins and their channels as gatekeepers of organ physiology. Cell Mol Life Sci 72:2775–2778. https://doi.org/10.1007/s00018-015-1958-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Evans WH, Martin PEM (2002) Gap junctions: structure and function (Review). Mol Membr Biol 19:121–136. https://doi.org/10.1080/09687680210139839

    Article  CAS  PubMed  Google Scholar 

  5. Peracchia C (2004) Chemical gating of gap junction channels: roles of calcium, pH and calmodulin. Biochim Biophys Acta Biomembr 1662:61–80. https://doi.org/10.1016/j.bbamem.2003.10.020

    Article  CAS  Google Scholar 

  6. Pantano S, Zonta F, Mammano F (2008) A fully atomistic model of the Cx32 connexon. PLoS One 3:1–11. https://doi.org/10.1371/journal.pone.0002614

    Article  CAS  Google Scholar 

  7. Yeager M, Harris AL (2007) Gap junction channel structure in the early 21st century: facts and fantasies. Curr Opin Cell Biol 19:521–528. https://doi.org/10.1016/j.ceb.2007.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bennett MVL, Contreras JE, Bukauskas FF, Sáez JC (2003) New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci 26:610–617

    Article  CAS  Google Scholar 

  9. Hung A, Yarovsky I (2011) Gap junction hemichannel interactions with zwitterionic lipid, anionic lipid, and cholesterol: molecular simulation studies. Biochemistry 50:1492–1504. https://doi.org/10.1021/bi1004156

    Article  CAS  PubMed  Google Scholar 

  10. Lopez W, Ramachandran J, Alsamarah A et al (2016) Mechanism of gating by calcium in connexin hemichannels. Proc Natl Acad Sci 201609378. https://doi.org/10.1073/pnas.1609378113

  11. Zonta F, Polles G, Zanotti G, Mammano F (2012) Permeation pathway of homomeric connexin 26 and connexin 30 channels investigated by molecular dynamics. J Biomol Struct Dyn 29:985–998. https://doi.org/10.1080/073911012010525027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang Y, Tang W, Ahmad S et al (2005) Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions. Proc Natl Acad Sci U S A 102:15201–15206. https://doi.org/10.1073/pnas.0501859102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ebihara L, Steiner E (1993) Properties of a nonjunctional current expressed from a rat connexin46 cDNA in Xenopus oocytes. J Gen Physiol 102:59–74

    Article  CAS  Google Scholar 

  14. Albano JMRJMR, Mussini N, Toriano R et al (2018) Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity. Comput Biol Chem 77:331–342. https://doi.org/10.1016/j.compbiolchem.2018.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bennett BC, Purdy MD, Baker KA et al (2016) An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels. Nat Commun 7:8770. https://doi.org/10.1038/ncomms9770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Beyer EC, Berthoud VM (2017) Gap junction structure: unraveled, but not fully revealed. F1000Research 6:568. https://doi.org/10.12688/f1000research.10490.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ebihara L, Liu X, Pal JD (2003) Effect of external magnesium and calcium on human connexin46 hemichannels. Biophys J 84:277–286. https://doi.org/10.1016/S0006-3495(03)74848-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cernak I, Radosevic P, Malicevic Z, Savic J (1995) Experimental magnesium depletion in adult rabbits caused by blast overpressure. Magnes Res 8:249–259

    CAS  PubMed  Google Scholar 

  19. Heath DL, Vink R (1996) Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration. Brain Res 738:150–153

    Article  CAS  Google Scholar 

  20. Murphy E, Steenbergen C, Levy LA et al (1989) Cytosolic free magnesium levels in ischemic rat heart. J Biol Chem 264:5622–5627

    CAS  PubMed  Google Scholar 

  21. Helpern JA, Vande Linde AM, Welch KM et al (1993) Acute elevation and recovery of intracellular [Mg2+] following human focal cerebral ischemia. Neurology 43:1577–1581

    Article  CAS  Google Scholar 

  22. Wood I, Albano JMR, Filho PLO et al (2018) A sumatriptan coarse-grained model to explore different environments: interplay with experimental techniques. Eur Biophys J 47:561–571. https://doi.org/10.1007/s00249-018-1278-2

    Article  CAS  PubMed  Google Scholar 

  23. Calì T, Frizzarin M, Luoni L et al (2017) The ataxia related G1107D mutation of the plasma membrane Ca2 + ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process. Biochim Biophys Acta Mol basis Dis 1863:165–173. https://doi.org/10.1016/j.bbadis.2016.09.007

    Article  CAS  PubMed  Google Scholar 

  24. Zonta F, Buratto D, Crispino G et al (2018) Cues to opening mechanisms from in silico electric field excitation of Cx26 hemichannel and in vitro mutagenesis studies in HeLa Transfectans. Front Mol Neurosci 11. https://doi.org/10.3389/fnmol.2018.00170

  25. Abraham MJ, Murtola T, Schulz R et al (2015) Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2:19–25. https://doi.org/10.1016/j.softx.2015.06.001

    Article  Google Scholar 

  26. Best RB, Zhu X, Shim J et al (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone ϕ, ψ and side-chain χ 1 and χ 2 dihedral angles. J Chem Theory Comput 8:3257–3273. https://doi.org/10.1021/ct300400x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Albano JMR, de Paula E, Pickholz M (2018) Molecular dynamics simulations to study drug delivery systems. Molecular Dynamics. InTech. https://doi.org/10.5772/intechopen.75748

  28. Wu Y, Tepper HL, Voth GA (2006) Flexible simple point-charge water model with improved liquid-state properties. J Chem Phys 124:024503. https://doi.org/10.1063/1.2136877

    Article  CAS  PubMed  Google Scholar 

  29. Mahoney MW, Jorgensen WL (2000) A five-site model for liquid water and the reproduction of the density anomaly by rigid, nonpolarizable potential functions. J Chem Phys 112:8910. https://doi.org/10.1063/1.481505

    Article  CAS  Google Scholar 

  30. Nosé S (1984) A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys 81:511. https://doi.org/10.1063/1.447334

    Article  Google Scholar 

  31. Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697. https://doi.org/10.1103/PhysRevA.31.1695

    Article  CAS  Google Scholar 

  32. Parrinello M, Rahman A (1982) Strain fluctuations and elastic constants. J Chem Phys 76:2662–2666. https://doi.org/10.1063/1.443248

    Article  CAS  Google Scholar 

  33. Ewald PP (1921) Die berechnung Optischer und Elektrostatisher Gitterpotentiale. Ann Phys 64:253–287

    Article  Google Scholar 

  34. Herce HD, Garcia AE, Darden T (2007) The electrostatic surface term:(I) periodic systems. J Chem Phys 126:124106

    Article  Google Scholar 

  35. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load balanced, and scalable molecular simulations. J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  36. Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665–W667. https://doi.org/10.1093/nar/gkh381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jo S, Kim T, Iyer V, Im W (2008) CHARMM GUI: a web based graphical user interface for CHARMM. J Comput Chem 29:1859–1865. https://doi.org/10.1002/jcc.20945

    Article  CAS  PubMed  Google Scholar 

  38. Wu EL, Cheng X, Jo S et al (2014) CHARMM-GUI Membrane Builder toward realistic biological membrane simulations. J Comput Chem 35:1997–2004. https://doi.org/10.1002/jcc.23702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Albano JMR (2019) Structure: Cx26 hemichannel embedded in a POPC bilayer. https://doi.org/10.5281/ZENODO.2717742

  40. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38. https://doi.org/10.1016/0263-7855(96)00018-5

    Article  CAS  PubMed  Google Scholar 

  41. Jones DE, Lund AM, Ghandehari H, Facelli JC (2016) Molecular dynamics simulations in drug delivery research: calcium chelation of G3.5 PAMAM dendrimers. Cogent Chem 2:1229830. https://doi.org/10.1080/23312009.2016.1229830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The Center for High Performance Computing at The Utah University provided computer resources for High Performance Computing, which has been partially funded by the NIH Shared Instrumentation Grant 1S10OD021644-01A1. JCF has been partially supported by the University of Utah Center for Clinical and Translational Science under NCATS Grant U01TR002538. MBF has been partially supported by the University of Buenos Aires Grant 20020170100456BA and PIP CONICET 11220130100377. JMRA has been partially supported by the Florencio Fiorini Foundation. MP has been partially supported by grants ANPCyT PICT2014- 3653, PIP CONICET0131-2014.

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Correspondence to Marta B. Ferraro.

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This paper belongs to Topical Collection QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)

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Albano, J.M.R., Facelli, J.C., Ferraro, M.B. et al. Magnesium interactions with a CX26 connexon in lipid bilayers. J Mol Model 25, 232 (2019). https://doi.org/10.1007/s00894-019-4121-5

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