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The adsorption of human defensin 5 on bacterial membranes: simulation studies

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Abstract

Human α-defensin 5 (HD5) is one of the important antimicrobial peptides (AMPs) used against a broad-spectrum of pathogens, especially Gram-negative bacteria. HD5 kills by disrupting and making a pore in the bacterial membrane. The presence of lipopolysaccharide (LPS), located on a membrane surface, is found to have an impact on HD5’s activity, where such binding mechanism in microscopic detail remains unclear. In this work, we therefore employed molecular dynamics (MD) simulations to investigate the binding mechanisms of HD5 on LPS in comparison to a bare DMPC lipid membrane. Two oligomers, dimer and tetramer, are studied here. Apparently, the membrane structure influences the protein binding affinity. HD5 binds tighter to a lipid membrane than LPS. Both dimeric and tetrameric HD5 can penetrate deeply into a phosphate layer in a lipid membrane, whereas only facial contacts are observed for LPS systems. The proteins appear to stay in the polar area instead of diving into a hydrophobic region. Furthermore, it happens in all cases that residues in the active region (A1, T2, R6, R13, R32) contribute to the membrane adsorption. The breakdown of tetramer into two dimers is also found. This implies that the dimer is more favorable for membrane binding. Moreover, both dimeric and tetrameric HD5 can significantly disrupt a LPS layer, whilst no serious distortion of lipid membrane is obtained. This emphasizes the importance of LPS on HD5 activity.

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Abbreviations

MD:

Molecular dynamics

LPS:

Lipopolysaccharide

HD5:

Human α-defensin 5

DMPC:

1,2-dimyristoyl-sn-glycero-3-phosphocholine

References

  1. Jung SW, Lee J, Cho AE (2017) Elucidating the bacterial membrane disruption mechanism of human alpha-defensin 5: a theoretical study. J Phys Chem B 121(4):741–748. https://doi.org/10.1021/acs.jpcb.6b11806

    Article  CAS  PubMed  Google Scholar 

  2. Nguyen LT, Haney EF, Vogel HJ (2011) The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol 29(9):464–472

    Article  CAS  PubMed  Google Scholar 

  3. Zhang L (2017) Different dynamics and pathway of disulfide bonds reduction of two human defensins, a molecular dynamics simulation study. Proteins: Struct Funct Bioinf 85(4):665–681

    Article  CAS  Google Scholar 

  4. Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6(6):551

    Article  CAS  PubMed  Google Scholar 

  5. Rajabi M, Ericksen B, Wu XJ, de Leeuw E, Zhao L, Pazgier M, Lu WY (2012) Functional determinants of human enteric alpha-defensin HD5 crucial role for hydrophobicity at dimer interface. J Biol Chem 287(26):21615–21627. https://doi.org/10.1074/jbc.M112.367995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. de Leeuw E, Burks SR, Li X, Kao JPY, Lu W (2007) Structure-dependent functional properties of human defensin 5. FEBS Lett 581(3):515–520

    Article  PubMed  PubMed Central  Google Scholar 

  7. de Leeuw E, Rajabi M, Zou G, Pazgier M, Lu W (2009) Selective arginines are important for the antibacterial activity and host cell interaction of human α-defensin 5. FEBS Lett 583(15):2507–2512

    Article  PubMed  Google Scholar 

  8. Rajabi M, de Leeuw E, Pazgier M, Li J, Lubkowski J, Lu W (2008) The conserved salt bridge in human α-defensin 5 is required for its precursor processing and proteolytic stability. J Biol Chem 283(31):21509–21518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wei G, de Leeuw E, Pazgier M, Yuan W, Zou G, Wang J, Ericksen B, Lu W-Y, Lehrer RI, Lu W (2009) Through the looking glass, mechanistic insights from enantiomeric human defensins. J Biol Chem 284:29180–29192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chileveru HR, Lim SA, Chairatana P, Wommack AJ, Chiang IL, Nolan EM (2015) Visualizing attack of Escherichia coli by the antimicrobial peptide human defensin 5. Biochemistry-Us 54(9):1767–1777. https://doi.org/10.1021/bi501483q

    Article  CAS  Google Scholar 

  11. Wommack AJ, Robson SA, Wanniarachchi YA, Wan A, Turner CJ, Wagner G, Nolan EM (2012) NMR solution structure and condition-dependent oligomerization of the antimicrobial peptide human defensin 5. Biochemistry-Us 51(48):9624–9637. https://doi.org/10.1021/bi301255u

    Article  CAS  Google Scholar 

  12. Lehrer RI, Jung G, Ruchala P, Andre S, Gabius HJ, Lu W (2009) Multivalent binding of carbohydrates by the human alpha-defensin, HD5. J Immunol 183(1):480–490. https://doi.org/10.4049/jimmunol.0900244

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Y, Cougnon FB, Wanniarachchi YA, Hayden JA, Nolan EM (2013) Reduction of human defensin 5 affords a high-affinity zinc-chelating peptide. ACS Chem Biol 8(9):1907–1911. https://doi.org/10.1021/cb400340k

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang C, Shen M, Zhang N, Wang S, Xu Y, Chen S, Chen F, Yang K, He T, Wang A, Su Y, Cheng T, Zhao J, Wang J (2016) Reduction impairs the antibacterial activity but benefits the LPS neutralization ability of human enteric defensin 5. Sci Rep 6:22875. https://doi.org/10.1038/srep22875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Scott MG, Vreugdenhil AC, Buurman WA, Hancock RE, Gold MR (2000) Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J Immunol 164(2):549–553

    Article  CAS  PubMed  Google Scholar 

  16. Hsu P-C, Jefferies D, Khalid S (2016) Molecular dynamics simulations predict the pathways via which pristine fullerenes penetrate bacterial membranes. J Phys Chem B 120(43):11170–11179. https://doi.org/10.1021/acs.jpcb.6b06615

    Article  CAS  PubMed  Google Scholar 

  17. Wommack AJ, Robson SA, Wanniarachchi YA, Wan A, Turner CJ, Wagner G, Nolan EM (2012) NMR solution structure and condition-dependent oligomerization of the antimicrobial peptide human defensin 5. Biochemistry 51(48):9624–9637

    Article  CAS  PubMed  Google Scholar 

  18. Oostenbrink C, Villa A, Mark AE, Gunsteren WFV (2004) A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J Comput Chem 25(13):1656–1676. https://doi.org/10.1002/jcc.20090

    Article  CAS  PubMed  Google Scholar 

  19. Jung SW, Lee J, Cho AE (2017) Elucidating the bacterial membrane disruption mechanism of human α-defensin 5: a theoretical study. J Phys Chem B 121(4):741–748

    Article  CAS  PubMed  Google Scholar 

  20. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38. https://doi.org/10.1016/0263-7855(96)00018-5

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge the financial support received from the Kasetsart University Research and Development Institute (KURDI), Bangkok, Thailand and from a Science Achievement Scholarship of Thailand (SAST). We also thank Prof Syma Khalid for her kind support.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand

    Tadsanee Awang & Prapasiri Pongprayoon

  2. Computational Biomodelling Laboratory for Agricultural Science and Technology (CBLAST), Kasetsart University, Bangkok, 10900, Thailand

    Prapasiri Pongprayoon

  3. Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900, Thailand

    Prapasiri Pongprayoon

Authors
  1. Tadsanee Awang
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  2. Prapasiri Pongprayoon
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Correspondence to Prapasiri Pongprayoon.

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Awang, T., Pongprayoon, P. The adsorption of human defensin 5 on bacterial membranes: simulation studies. J Mol Model 24, 273 (2018). https://doi.org/10.1007/s00894-018-3812-7

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