Interaction of heparins and dextran sulfates with a mesoscopic protein nanopore.
A mechanism of how polyanions influence the channel formed by Staphylococcus aureus alpha-hemolysin is described. We demonstrate that the probability of several types of polyanions to block the ion channel depends on the presence of divalent cations and the polyanion molecular weight and concentration. For heparins, a 10-fold increase in molecular weight decreases the half-maximal inhibitory concentration, IC(50), nearly 10(4)-fold. Dextran sulfates were less effective at blocking the channel. The polyanions are significantly more effective at reducing the conductance when added to the trans side of this channel. Lastly, the effectiveness of heparins on the channel conductance correlated with their influence on the zeta-potential of liposomes. A model that includes the binding of polyanions to the channel-membrane complex via Ca(2+)-bridges and the asymmetry of the channel structure describes the data adequately. Analysis of the single channel current noise of wild-type and site-directed mutant versions of alpha-hemolysin channels suggests that a single polyanion enters the pore due to electrostatic forces and physically blocks the ion conduction path. The results might be of interest for pharmacology, biomedicine, and research aiming to design mesoscopic pore blockers.
Teixeira
Luciana R
LR
Laboratory of Membrane Biophysics, Department of Biophysics, Federal University of Pernambuco, Recife, Brazil.
Merzlyak
Petr G
PG
Valeva
Angela
A
Krasilnikov
Oleg V
OV
D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004553:Electric Conductivity; D006460:Hemolysin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D049329:Nanostructures / Q000737:chemistry*; D016062:Porosity; D011485:Protein Binding
D001427:Bacterial Toxins; D003911:Dextrans; D006460:Hemolysin Proteins; D008051:Lipid Bilayers; D008081:Liposomes; C021091:staphylococcal alpha-toxin; D006493:Heparin; D003545:Cysteine