Antimicrobial Protegrin 1 Forms Ion Channels Molecular Dynamic Simulation, Atomic Force Microscopy, and Electrical Conductance Studies英文文献.pdfVIP

2644 Biophysical Journal Volume 98 June 2010 2644–2652 Antimicrobial Protegrin-1 Forms Ion Channels: Molecular Dynamic Simulation, Atomic Force Microscopy, and Electrical Conductance Studies Ricardo Capone,† 6 Mirela Mustata,† 6 Hyunbum Jang,‡ 6 Fernando Teran Arce,† Ruth Nussinov,‡§ 6* and Ratnesh Lal† 6* †Center for Nanomedicine and Department of Medicine, University of Chicago, Chicago, Illinois; ‡Center for Cancer Research Nanobiology Program, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland; and §Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 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 b-sheet AMPs. Antibiotic activity of AMPs involves cell membrane damage, yet their membrane interactions, their 3D membrane-associated structures and the mechanism under- lying 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 exper- imental evidence that PG-1, a b-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 struc- tures 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 st