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Effects of cholesterol on chlorzoxazone translocation across POPC bilayer

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Abstract

Cholesterol plays a crucial role in modulating the physicochemical properties of membranes, thus influencing the membrane transport of drugs. In this paper, the effects caused by cholesterol on the membrane transport of chlorzoxazone (CZX), a centrally acting muscle relaxant drug, were probed through molecular dynamics simulations. POPC was selected as the model lipid, and three different cholesterol concentrations (0%, 20%, and 50% CHOL) were considered. The outcomes reveal that the area per lipid of POPC decreases and the order parameter increases with enhanced concentration of CHOL. CZX prefers to localize at the interface between the headgroup region and the hydrophobic tail region of POPC, and the main energy barrier occurs in the hydrophobic region. The impact of CHOL on the free energy profile is correlated with concentration: low concentration facilitates CZX permeation, while high concentration hinders CZX permeation. Our findings coincide with experimental results, enhancing the mechanism understanding of how drug molecules are transported through membranes in the presence of CHOL.

Graphical abstract

• The effects caused by cholesterol (CHOL) on the membrane transport of chlorzoxazone (CZX) were studied.

• Low CHOL concentration facilitates CZX permeation, while high concentration hinders CZX permeation.

• Our findings improve the mechanism understanding of CHOL effects on CZX translocation across membrane.

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All relevant data are within the paper and its Supporting information file.

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GROMACS 5.0.

References

  1. Seydel JK, Wiese M (2002) Drug-membrane interactions: analysis, drug distribution, modeling. Wiley-VCH Verlag GmbH & Co. KGaA

  2. Tattrie NH, Bennet JR, Cyr R (1968) Maximum and minimum values for lecithin classes from various biological sources. Can J Biochem 46:819–824

    Article  CAS  Google Scholar 

  3. Patrick JW, Gamez RC, Russell DH (2016) The influence of lipid bilayer physicochemical properties on gramicidin A conformer preferences. Biophys J 110(8):1826–1835

    Article  CAS  Google Scholar 

  4. Favela-Rosales F, Carbajal-Tinoco MD, Ortega-Blake I (2014) Liquid-ordered phase formation in cholesterol-Popc bilayer: all-atom molecular dynamics simulations. Biophys J 106(2):80a

    Article  Google Scholar 

  5. Cournia Z, Ullmann M, Smith JC (2007) Differential effects of cholesterol, ergosterol and lanosterol on a dipalmitoyl phosphatidylcholine membrane: a molecular dynamics simulation study. J Phys Chem B 111(7):1786–1801

    Article  CAS  Google Scholar 

  6. Plesnar E, Subczynski WK, Pasenkiewicz-Gierula M (2012) Saturation with cholesterol increases vertical order and smoothes the surface of the phosphatidylcholine bilayer: a molecular simulation study. Biochim Biophys Acta Biomembr 1818:520–529

    Article  CAS  Google Scholar 

  7. Pandit SA, Chiu S-W, Jakobsson E, Grama A, Scott HL (2008) Cholesterol packing around lipids with saturated and unsaturated chains. Langmuir 24(13):6858–6865

    Article  CAS  Google Scholar 

  8. Pucadyil TJ, Chattopadhyay A (2006) Effect of cholesterol on lateral diffusion of fluorescent lipid probes in native hippocampal membranes. Chem Phys Lipids 43:11–21

    Article  Google Scholar 

  9. Berka K, Paloncyova M, Anzenbacher P, Otyepka M (2013) Behavior of human cytochromes P450 on lipid membranes. J Phys Chem B 117:11556–11564

    Article  CAS  Google Scholar 

  10. Berka K, Hendrychova T, Anzenbacher P, Otyepka M (2011) Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site. J Phys Chem A 115:11248–11255

    Article  CAS  Google Scholar 

  11. Navrátilová V, Paloncýová M, Kajšová M, Berka K, Otyepk M (2015) Effect of cholesterol on the structure of membrane-attached cytochrome P450 3A4. J Chem Inf Model 55(3):628–635

    Article  Google Scholar 

  12. Zhang L, Bennett WFD, Zheng T, Ouyang PK, Ouyang X, Qiu X, Luo A, Karttunen M, Chen P (2016) Effect of cholesterol on cellular uptake of cancer drugs pirarubicin and ellipticine. J Phys Chem B 120(12):3148–3156

    Article  CAS  Google Scholar 

  13. Poojari C, Zak A, Dzieciuch-Rojek M, Bunker A, Kepczynski M, Róg T (2020) Cholesterol reduces partitioning of antifungal drug itraconazole into lipid bilayers. J Phys Chem B 124(11):2139–2148

    Article  CAS  Google Scholar 

  14. Khajeh A, Modarress H (2014) Effect of cholesterol on behavior of 5-fluorouracil (5-FU) in a DMPC lipid bilayer, a molecular dynamics study. Biophys Chem 187-188:43–50

    Article  CAS  Google Scholar 

  15. Yamada A, Shimizu N, Hikima T, Takata M, Kobayashi T, Takahashi (2016) Effect of cholesterol on the interaction of cytochrome P450 substrate drug chlorzoxazone with the phosphatidylcholine bilayer. Biochem 55(28):3888–3898

    Article  CAS  Google Scholar 

  16. Paloncyova M, Berka K, Otyepka M (2013) Molecular insight into affinities of drugs and their metabolites to lipid bilayers. J Phys Chem B 117:2403–2410

    Article  CAS  Google Scholar 

  17. Martínez L, Andrade R, Birgin E, Martinez J (2009) PACKMOL: a package for building initial configurations for molecular dynamics simulations. J Comput Chem 30:2157–2164

    Article  Google Scholar 

  18. Ferreira TM, Coreta-Gomes F, Ollila OHS, Moreno MJ, Vaz WLC, Topgaard D (2013) Cholesterol and POPC segmental order parameters in lipid membranes: solid state 1H-13C NMR and MD simulation studies. Phys Chem Chem Phys 15(6):1976–1989

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through muti-level parallelism from laptops to supercomputers. SoftwareX 1-2:19–25

    Article  Google Scholar 

  21. Schuettelkopf AW, Aalten DMF (2004) PRODRG-a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D60:1355–1363

    CAS  Google Scholar 

  22. Kumar S, Rosenberg JM, Bouzida D, Swendsen RH, Kollman PA (1992) The weighted histogram analysis method for free-energy calculations on biomolecules: I. The method. J Comput Chem 13:1011–1021

    Article  CAS  Google Scholar 

  23. Hub JS, de Groot BL, van der Spoel D (2010) g_wham–a free weighted histogram analysis implementation including robust error and autocorrelation estimates. J Chem Theory Comput 6:3713–3720

    Article  CAS  Google Scholar 

  24. Lantzsch G, Binder H, Heerklotz H, Wendling M, Klose G (1996) Surface areas and packing constraints in POPC/C12EOn membranes. A time-resolved fluorescence study. Biophys Chem 58:289–302

    Article  CAS  Google Scholar 

  25. Poger D, Mark AE (2010) On the validation of molecular dynamics simulations of saturated and cis-monounsaturated phosphatidylcholine lipid bilayers: a comparison with experiment. J Chem Theory Comput 6:325–336

    Article  CAS  Google Scholar 

  26. Liu Y, Zhang D, Zhang Y, Tang Y, Xu L, He H, Wu J, Zheng J (2020) Molecular dynamics simulations of cholesterol effects on the interaction of hIAPP with lipid bilayer. J Phys Chem B 124(36):7830–7841

    Article  CAS  Google Scholar 

  27. Leite NB, Mattins DB, Fazani VE, Vieira MR, Dos Santos Cabrera MP (2018) Cholesterol modulates curcumin partitioning and membrane effects. Biochim Bio Phys Acat-Biomembr 1860(11):2320–2328

    Article  CAS  Google Scholar 

  28. Meng F, Wang H (2017) The permeability enhancing mechanism of menthol on skin lipids: a molecular dynamics simulation study. J Mol Model 23:279

    Article  Google Scholar 

  29. Loura LMS, do Canto AMTM, Martins J (2013) Sensing hydration and behavior of pyrene in POPC and POPC/cholesterol bilayers: a molecular dynamics study. Biochim Biophys Acta 1828:1094–1101

    Article  CAS  Google Scholar 

  30. Smondyrew AM, Berkowitz ML (1999) Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: molecular dynamics simulation. Biophys J 77:2075–2089

    Article  Google Scholar 

  31. Sun D, Lin X, Gu N (2014) Cholesterol affects C60 translocation across lipid bilayers. Soft Matter 13

  32. Zocher F, van der Spoel D, Pohl P, Hub JS (2013) Local partition coefficients govern solute permeability of cholesterol-containing membranes. Biophys J 105:2760–2770

    Article  CAS  Google Scholar 

  33. Jedlovszky P, Mezei M (2003) Effect of cholesterol on the properties of phospholipid membranes. 2. Free energy profile of small molecules. J Phys Chem B 107(22):5322–5332

    Article  CAS  Google Scholar 

  34. Kang M, Loverde SM (2014) Molecular simulation of the concentration-dependent interaction of hydrophobic drugs with model cellular membranes. J Phys Chem B 118:11965–11972

    Article  CAS  Google Scholar 

  35. Wang H, Meng F (2016) Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study. Mol Simul 42:1292–1297

    Article  CAS  Google Scholar 

  36. Wang H, Meng F (2016) Molecular simulation study on concentration effects of rofecoxib with POPC bilayer. J Mol Graph Model 70:94–99

    Article  CAS  Google Scholar 

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Acknowledgments

The calculations were performed using the TianHe-1(A) supercomputer at the National Supercomputing Center in Tianjin.

Funding

This work was supported by the Science and Technology Program of Tianjin (Grant Numbers 18ZXXYSY00040 and 19YFZCSY00620) and Tianjin 131 Talent Project.

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Authors and Affiliations

  1. Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300301, People’s Republic of China

    Jing Yuan & Fancui Meng

  2. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300301, People’s Republic of China

    Fancui Meng

Authors
  1. Jing Yuan
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  2. Fancui Meng
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Contributions

F Meng conceived and designed the simulation. J Yuan performed the calculations and analysis. Both authors contributed to the first draft of the manuscript.

Corresponding author

Correspondence to Fancui Meng.

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Yuan, J., Meng, F. Effects of cholesterol on chlorzoxazone translocation across POPC bilayer. J Mol Model 27, 146 (2021). https://doi.org/10.1007/s00894-021-04777-2

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