Evaluation of the Binding Mechanism of Human Defensin 5 in a Bacterial Membrane: A Simulation Study

Int J Mol Sci. 2021 Nov 17;22(22):12401. doi: 10.3390/ijms222212401.


Human α-defensin 5 (HD5) is a host-defense peptide exhibiting broad-spectrum antimicrobial activity. The lipopolysaccharide (LPS) layer on the Gram-negative bacterial membrane acts as a barrier to HD5 insertion. Therefore, the pore formation and binding mechanism remain unclear. Here, the binding mechanisms at five positions along the bacterial membrane axis were investigated using Molecular Dynamics. (MD) simulations. We found that HD5 initially placed at positions 1 to 3 moved up to the surface, while HD5 positioned at 4 and 5 remained within the membrane interacting with the middle and inner leaflet of the membrane, respectively. The arginines were key components for tighter binding with 3-deoxy-d-manno-octulosonic acid (KDO), phosphates of the outer and inner leaflets. KDO appeared to retard the HD5 penetration.

Keywords: antimicrobial peptides; human defensin 5; lipopolysaccharide; molecular dynamics simulations.

MeSH terms

  • Amino Acid Sequence
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / metabolism*
  • Arginine / metabolism
  • Cell Membrane / metabolism*
  • Gram-Negative Bacteria / metabolism*
  • Humans
  • Hydrogen Bonding
  • Lipopolysaccharides / metabolism
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Multimerization
  • Sugar Acids / metabolism
  • alpha-Defensins / chemistry
  • alpha-Defensins / metabolism*


  • Anti-Infective Agents
  • DEFA5 protein, human
  • Lipopolysaccharides
  • Sugar Acids
  • alpha-Defensins
  • 2-keto-3-deoxyoctonate
  • Arginine