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Published on: July 4, 2016
Antimicrobial protegrin-1 forms ion channels: molecular dynamic simulation, atomic force microscopy, and electrical
Ricardo Capone1, Mirela Mustata, Hyunbum Jang
1Center for Nanomedicine and Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Abstract:
Antimicrobial peptides (AMPs) are an emerging class of antibiotics for controlling health effects of antibiotic-resistant microbial strains. Protegrin-1 (PG-1) is a model antibiotic among beta-sheet AMPs. Antibiotic activity of AMPs involves cell membrane damage, yet their membrane interactions, their 3D membrane-associated structures and the mechanism underlying their ability to disrupt cell membrane are poorly understood. Using complementary approaches, including molecular dynamics simulations, atomic force microscopy (AFM) imaging, and planar lipid bilayer reconstitution, we provide computational and experimental evidence that PG-1, a beta-hairpin peptide, forms ion channels. Simulations indicate that PG-1 forms channel-like structures with loosely attached subunits when reconstituted in anionic lipid bilayers. AFM images show the presence of channel-like structures when PG-1 is reconstituted in dioleoylphosphatidylserine/palmitoyloleoyl phosphatidylethanolamine bilayers or added to preformed bilayers. Planar lipid bilayer electrical recordings show multiple single channel conductances that are consistent with the heterogeneous oligomeric channel structures seen in AFM images. PG-1 channel formation seems to be lipid-dependent: PG-1 does not easily show ion channel electrical activity in phosphatidylcholine membranes, but readily shows channel activity in membranes rich in phosphatidylethanolamine or phosphatidylserine. The combined results support a model wherein the beta-hairpin PG-1 peptide acts as an antibiotic by altering cell ionic homeostasis through ion channel formation in cell membranes.
Insights
Antimicrobial peptides like Protegrin-1 (PG-1) form ion channels in cell membranes, damaging them to combat antibiotic-resistant bacteria. This study reveals PG-1
Area of Science:
- Biophysics
- Molecular Biology
- Drug Discovery
Background:
- Antimicrobial peptides (AMPs) are crucial for combating antibiotic-resistant microbes.
- Protegrin-1 (PG-1), a beta-sheet AMP, serves as a model for studying membrane disruption.
- The precise mechanisms of AMP membrane interaction and structure remain unclear.
Purpose of the Study:
- To investigate the membrane interactions and structure of Protegrin-1 (PG-1).
- To elucidate the mechanism by which PG-1 disrupts cell membranes.
- To provide computational and experimental evidence for PG-1's antibiotic action.
Main Methods:
- Molecular dynamics simulations
- Atomic force microscopy (AFM) imaging
- Planar lipid bilayer reconstitution and electrical recordings
Main Results:
- PG-1 forms channel-like structures in anionic lipid bilayers.
- AFM and electrical recordings confirm heterogeneous oligomeric channel formation.
- PG-1's ion channel activity is dependent on lipid composition, favoring phosphatidylethanolamine and phosphatidylserine.
Conclusions:
- PG-1, a beta-hairpin peptide, functions as an antibiotic by forming ion channels.
- These channels disrupt cell ionic homeostasis, leading to membrane damage.
- Lipid-dependent channel formation is a key aspect of PG-1's antimicrobial mechanism.
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