TY - JOUR
T1 - On the nature of antimicrobial activity
T2 - A model for protegrin-1 pores
AU - Langham, Allison A.
AU - Ahmad, Abdallah Sayyed
AU - Kaznessis, Yiannis N.
PY - 2008/4/2
Y1 - 2008/4/2
N2 - We conducted over 150 ns of simulation of a protegrin-1 octamer pore in a lipid bilayer composed of palmitoyloleoyl-phosphatidylethanolamine (POPE) and palmitoyloleoyl-phosphatidylglycerol (POPG) lipids mimicking the inner membrane of a bacterial cell. The simulations improve on a model of a pore proposed from recent NMR experiments and provide a coherent understanding of the molecular mechanism of antimicrobial activity. Although lipids tilt somewhat toward the peptides, the simulated protegrin-1 pore more closely follows the barrel-stave model than the toroidal-pore model. The movement of ions is investigated through the pore. The pore selectively allows negatively charged chloride ions to pass through at an average rate of one ion every two nanoseconds. Only two events are observed of sodium ions crossing through the pore. The potential of mean force is calculated for the water and both ion types. It is determined that the chloride ions move through the pore with ease, similarly to the water molecules with the exception of a zone of restricted movement midway through the pore. In bacteria, ions moving through the pore will compromise the integrity of the transmembrane potential. Without the transmembrane potential as a countermeasure, water will readily flow inside the higher osmolality cytoplasm. We determine that the diffusivity of water through a single PG-1 pore is sufficient to cause fast cell death by osmotic lysis.
AB - We conducted over 150 ns of simulation of a protegrin-1 octamer pore in a lipid bilayer composed of palmitoyloleoyl-phosphatidylethanolamine (POPE) and palmitoyloleoyl-phosphatidylglycerol (POPG) lipids mimicking the inner membrane of a bacterial cell. The simulations improve on a model of a pore proposed from recent NMR experiments and provide a coherent understanding of the molecular mechanism of antimicrobial activity. Although lipids tilt somewhat toward the peptides, the simulated protegrin-1 pore more closely follows the barrel-stave model than the toroidal-pore model. The movement of ions is investigated through the pore. The pore selectively allows negatively charged chloride ions to pass through at an average rate of one ion every two nanoseconds. Only two events are observed of sodium ions crossing through the pore. The potential of mean force is calculated for the water and both ion types. It is determined that the chloride ions move through the pore with ease, similarly to the water molecules with the exception of a zone of restricted movement midway through the pore. In bacteria, ions moving through the pore will compromise the integrity of the transmembrane potential. Without the transmembrane potential as a countermeasure, water will readily flow inside the higher osmolality cytoplasm. We determine that the diffusivity of water through a single PG-1 pore is sufficient to cause fast cell death by osmotic lysis.
UR - http://www.scopus.com/inward/record.url?scp=41549125949&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41549125949&partnerID=8YFLogxK
U2 - 10.1021/ja0780380
DO - 10.1021/ja0780380
M3 - Article
C2 - 18335931
AN - SCOPUS:41549125949
VL - 130
SP - 4338
EP - 4346
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 13
ER -