Molecular dynamics investigation of the influence of anionic and zwitterionic interfaces on antimicrobial peptides' structure: Implications for peptide toxicity and activity

Himanshu Khandelia, Yiannis N. Kaznessis

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Molecular dynamics simulations of three related helical antimicrobial peptides have been carried out in zwitterionic diphosphocholine (DPC) micelles and anionic sodiumdodecylsulfate (SDS) micelles. These systems can be considered as model mammalian and bacterial membrane interfaces, respectively. The goal of this study is to dissect the differences in peptide composition which make the mutant peptides (novispirin-G10 and novispirin-T7) less toxic than the parent peptide ovispirin (OVIS), although all three peptides have highly antibacterial properties. Compared to G10 and T7, OVIS inserts deepest into the DPC micelle. This correlates well with the lesser toxicity of G10 and T7. There is strong evidence which suggests that synergistic binding of hydrophobic residues drives binding of OVIS to the micelle. The helical content of G10 and T7 is reduced in the presence of DPC, and this leads to less amphipathic peptide structures, which bind weakly to the micelle. Simulations in SDS were carried out to compare the influence of membrane electrostatics on peptide structure. All three peptides bound strongly to SDS, and retained helical form. This corresponds well with their equally potent antibacterial properties. Based on the simulations, we argue that secondary structure stability often leads to toxic properties. We also propose that G10 and T7 operate by the carpet mechanism of cell lysis. Toxicity of peptides operating by the carpet mechanism can be attenuated by reducing the peptide helical content. The simulations successfully capture experimental binding states, and the different depths of binding of the three peptides to the two micelles correlate with their antibacterial and toxic properties.

Original languageEnglish (US)
Pages (from-to)1192-1200
Number of pages9
JournalPeptides
Volume27
Issue number6
DOIs
StatePublished - Jun 2006

Bibliographical note

Funding Information:
This work was supported by grants from NIH (GM 070989) and NSF (EEC-0234112). Computational support from the Minnesota Supercomputing Institute (MSI) is gratefully acknowledged. This work was also partially supported by National Computational Science Alliance under MCA04T033 and utilized the marvel cluster at the Pittsburgh Supercomputing Center. We thank Prof. Alan Waring for useful discussions.

Keywords

  • AMP
  • AMP activity
  • AMP toxicity
  • DPC micelle
  • Molecular dynamics simulations
  • Ovispirin-1
  • Peptide-membrane interactions
  • SDS micelle
  • Secondary structure induction

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