Conformational study of the protegrin-1 (PG-1) dimer interaction with lipid bilayers and its effect.
BACKGROUND
Protegrin-1 (PG-1) is known as a potent antibiotic peptide; it prevents infection via an attack on the membrane surface of invading microorganisms. In the membrane, the peptide forms a pore/channel through oligomerization of multiple subunits. Recent experimental and computational studies have increasingly unraveled the molecular-level mechanisms underlying the interactions of the PG-1 beta-sheet motifs with the membrane. The PG-1 dimer is important for the formation of oligomers, ordered aggregates, and for membrane damaging effects. Yet, experimentally, different dimeric behavior has been observed depending on the environment: antiparallel in the micelle environment, and parallel in the POPC bilayer. The experimental structure of the PG-1 dimer is currently unavailable.


RESULTS
Although the beta-sheet structures of the PG-1 dimer are less stable in the bulk water environment, the dimer interface is retained by two intermolecular hydrogen bonds. The formation of the dimer in the water environment implies that the pathway of the dimer invasion into the membrane can originate from the bulk region. In the initial contact with the membrane, both the antiparallel and parallel beta-sheet conformations of the PG-1 dimer are well preserved at the amphipathic interface of the lipid bilayer. These beta-sheet structures illustrate the conformations of PG-1 dimer in the early stage of the membrane attack. Here we observed that the activity of PG-1 beta-sheets on the bilayer surface is strongly correlated with the dimer conformation. Our long-term goal is to provide a detailed mechanism of the membrane-disrupting effects by PG-1 beta-sheets which are able to attack the membrane and eventually assemble into the ordered aggregates.


CONCLUSIONS
In order to understand the dimeric effects leading to membrane damage, extensive molecular dynamics (MD) simulations were performed for the beta-sheets of the PG-1 dimer in explicit water, salt, and lipid bilayers composed of POPC lipids. Here, we studied PG-1 dimers when organized into a beta-sheet motif with antiparallel and parallel beta-sheet arrangements in an NCCN packing mode. We focus on the conformations of PG-1 dimers in the lipid bilayer, and on the correlation between the conformations and the membrane disruption effects by PG-1 dimers. We investigate equilibrium structures of the PG-1 dimers in different environments in the early stage of the dimer invasion. The dimer interface of the antiparallel beta-sheets is more stable than the parallel beta-sheets, similar to the experimental observation in micelle environments. However, we only observe membrane disruption effects by the parallel beta-sheets of the PG-1 dimer. This indicates that the parallel beta-sheets interact with the lipids with the beta-sheet plane lying obliquely to the bilayer surface, increasing the surface pressure in the initial insertion into the lipid bilayer. Recent experimental observation verified that parallel PG-1 dimer is biologically more active to insert into the POPC lipid bilayer.
Jang
Hyunbum
H
Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA. jangh@ncifcrf.gov <jangh@ncifcrf.gov>
Ma
Buyong
B
Nussinov
Ruth
R
D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D019281:Dimerization; D006860:Hydrogen Bonding; D008051:Lipid Bilayers; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D011506:Proteins; C094880:protegrin-1