Conformational Analysis of a Synthetic Antimicrobial Peptide in Water and Membrane-Mimicking Solvents: A Molecular Dynamics Simulation Study

  • Sandro L. ForniliEmail author
  • Rita Pizzi
  • Davide Rebeccani


We have investigated structural and dynamic properties of the synthetic peptide hlF1-11 (GRRRSVQWCA, i.e., the first 11 N-terminal amino acids of the human lactoferrin protein) in water, 250 mM NaCl solution, 50% (V/V) water–trifluoroethanol mixture, and in the membrane mimetic 4:4:1 methanol–chloroform–water mixture. For comparison, we have also performed analogous simulations for the biologically inactive control peptide featuring Ala substitutions in the 2, 3, 6 and 9 positions of the hlF1-11 sequence. Statistical analyses of the trajectories indicate that only in the membrane-mimicking medium hlF1-11 adopts preferentially a conformation suitable to interact effectively with the membrane. In this conformation the peptide cationic region is rather flexible and elongated, while the C-terminal hydrophobic moiety appears as a more rigid hairpin-shaped loop approximately perpendicular to the cationic region. No such conformation is statistically relevant for the control peptide.


Antimicrobial peptides Human lactoferrin Molecular dynamics simulation Membrane-mimicking solvents 


  1. Abbate S, Barlati S, Colombi M, Fornili SL, Francescato P, Gangemi F et al (2006) Study of conformational properties of a biologically active peptide of fibronectin by circular dichroism, NMR and molecular dynamics simulation. Phys Chem Chem Phys 8:4668–4677CrossRefPubMedGoogle Scholar
  2. Allen MP, Tildesley TJ (1987) Computer simulation of liquids. Clarendon Press, OxfordGoogle Scholar
  3. Bergman DL, Laaksonen L, Laaksonen A (1997) Visualization of solvation structures in liquid mixtures. J Mol Graph Model 15:301–306CrossRefPubMedGoogle Scholar
  4. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250CrossRefPubMedGoogle Scholar
  5. Brouwer CPJM, Welling MM (2008) Various routes of administration of 99mTc-labeled synthetic lactoferrin antimicrobial peptide hlF1-11 enables monitoring and effective killing of multidrug-resistant Staphylococcus aureus infections in mice. Peptides 29:1109–1117CrossRefPubMedGoogle Scholar
  6. Caldwell JW, Kollman PA (1995) Structure and properties of neat liquids using nonadditive molecular dynamics: water, methanol and N-methylacetamide. J Phys Chem 99:6208–6219CrossRefGoogle Scholar
  7. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R et al (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefPubMedGoogle Scholar
  8. Case DA, Darden TA, Cheatham TE, Simmerling CL, Wang J, Duke RE et al (2008) AMBER 10. University of California, San FranciscoGoogle Scholar
  9. Chan DIR, Prenner EJ, Vogel HJ (2006) Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action. Biochim Biophys Acta 1758:1184–1202CrossRefPubMedGoogle Scholar
  10. Dijkshoorn L, Brouwer CPJM, Bogaards SJP, Nemec A, van den Broek PJ, Nibbering PH (2004) The synthetic N-terminal peptide of human lactoferrin, hLF(1-11), is highly effective against experimental infection caused by multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 48:4919–4921CrossRefPubMedGoogle Scholar
  11. Fox T, Kollman PA (1998) Application of the RESP methodology in the parametrization of organic solvents. J Phys Chem B 102:8070–8079CrossRefGoogle Scholar
  12. Gangemi F, Longhi G, Abbate S, Lebon F, Cordone R, Ghilardi GP, Fornili SL (2008) Molecular dynamics simulation of aqueous solutions of 26-unit segments of p(NIPAAm) and of p(NIPAAm) “doped” with amino acid based comonomers. J Phys Chem B 112:11896–11906CrossRefPubMedGoogle Scholar
  13. Haney EF, Hunter HN, Matsuzaki K, Vogel HJ (2009) Solution NMR studies of amphibian antimicrobial peptides: linking structure to function? Biochim Biophys Acta 1788:1639–1665CrossRefPubMedGoogle Scholar
  14. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38CrossRefPubMedGoogle Scholar
  15. Ibragimova GT, Wade RC (1998) Importance of explicit salt ions for protein stability in molecular dynamics simulations. Biophys J 74:2906–2911CrossRefPubMedGoogle Scholar
  16. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparisons of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  17. Langham AA, Khandelia H, Schuster B, Waring AJ, Leher RI, Kaznessis YN (2008) Correlation between simulated physicochemical properties and hemolycity of protegrin-like antimicrobial peptides: predicting experimental toxicity. Peptides 29:1085–1093CrossRefPubMedGoogle Scholar
  18. Mottamal M, Shen S, Guembe C, Krilov G (2007) Solvation of transmembrane proteins by isotropic membrane mimetics: a molecular dynamics study. J Phys Chem 111:11285–11296Google Scholar
  19. Nibbering PH, Ravensbergen E, Welling MM, van Berkel L, van Berkel PHC, Pauwels EKJ, Nuijens JH (2001) Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant bacteria. Infect Immun 69:1469–1476CrossRefPubMedGoogle Scholar
  20. Onufriev A, Bashford D, Case DA (2004) Exploring protein native states and large-scale conformational changes with a modified generalized Born model. Proteins 55:383–394CrossRefPubMedGoogle Scholar
  21. Peterson NA, Arcus VL, Anderson BF, Tweedie JW, Jameson GB, Baker EN (2002) “Dilysine trigger” in transferrins probed by mutagenesis of lactoferrin: crystal structures of the R210G, R210E and R210L mutants of human lactoferrin. Biochemistry 41:14167–14175CrossRefPubMedGoogle Scholar
  22. Powers J-PS, Hancock REW (2003) The relationship between peptide structure and antibacterial activity. Peptides 24:1681–1691CrossRefPubMedGoogle Scholar
  23. Ruotolo BT, Russell DH (2004) Gas-phase conformations of proteolytically derived protein fragments: influence of solvent on peptide conformation. J Phys Chem B 108:15321–15331CrossRefGoogle Scholar
  24. Shao J, Tanner SW, Thompson N, Cheatam TE (2007) Clustering molecular dynamics trajectories: 1. Characterizing the performance of different clustering algorithms. J Chem Theory Comput 3:2312–2334CrossRefGoogle Scholar
  25. Voss NR, Gerstein M (2005) Calculation of standard atomic volumes for RNA and comparison with proteins: RNA is packed more tightly. J Mol Biol 346:477–492CrossRefPubMedGoogle Scholar
  26. Wang K-R, Zhang B-Z, Zhang W, Yan J-X, Li J, Wang R (2008) Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29:963–968CrossRefPubMedGoogle Scholar
  27. Wickstrom L, Okur A, Simmerling C (2009) Evaluating the performance of the ff99SB force field based on NMR scalar coupling data. Biophys J 97:853–856CrossRefPubMedGoogle Scholar
  28. Yeaman MR, Yount NY (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55:27–55CrossRefPubMedGoogle Scholar
  29. Zhou N, Tieleman DP, Volfel HJ (2004) Molecular dynamics simulations of bovine lactoferrin: turning a helix into a sheet. Biometals 17:217–223CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sandro L. Fornili
    • 1
    • 2
    • 3
    Email author
  • Rita Pizzi
    • 1
  • Davide Rebeccani
    • 1
  1. 1.Dipartimento di Tecnologie dell’InformazioneUniversità di MilanoCremaItaly
  2. 2.CISIMilanItaly
  3. 3.CNISMRomeItaly

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