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

  • Tadsanee Awang
  • Prapasiri PongprayoonEmail author
Original Paper


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.


Antimicrobial peptides Human defensin 5 LPS Molecular dynamics simulations Host-defense peptide 



Molecular dynamics




Human α-defensin 5





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.

Supplementary material

894_2018_3812_MOESM1_ESM.docx (338 kb)
ESM 1 (DOCX 337 kb)


  1. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Nguyen LT, Haney EF, Vogel HJ (2011) The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol 29(9):464–472CrossRefGoogle Scholar
  3. 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):665–681CrossRefGoogle Scholar
  4. 4.
    Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6(6):551CrossRefGoogle Scholar
  5. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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):515–520CrossRefGoogle Scholar
  7. 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):2507–2512CrossRefGoogle Scholar
  8. 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):21509–21518CrossRefGoogle Scholar
  9. 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 284:29180–29192CrossRefGoogle Scholar
  10. 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. CrossRefGoogle Scholar
  11. 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. CrossRefGoogle Scholar
  12. 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. CrossRefGoogle Scholar
  13. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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):549–553CrossRefGoogle Scholar
  16. 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. CrossRefGoogle Scholar
  17. 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):9624–9637CrossRefGoogle Scholar
  18. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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):741–748CrossRefGoogle Scholar
  20. 20.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceKasetsart UniversityBangkokThailand
  2. 2.Computational Biomodelling Laboratory for Agricultural Science and Technology (CBLAST)Kasetsart UniversityBangkokThailand
  3. 3.Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced StudiesKasetsart UniversityBangkokThailand

Personalised recommendations