56 research outputs found

    Structure-Activity Relationships of Influenza a M2 Inhibitors

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    Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: opposing responses to isoflurane

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    <p>Abstract</p> <p>Background</p> <p>The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature.</p> <p>Results</p> <p>In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount.</p> <p>Conclusions</p> <p>The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane.</p

    Model Channel Ion Currents in NaCl - SPC/E Solution with Applied-Field Molecular Dynamics

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    Using periodic boundary conditions and a constant applied field, we have simulated current flow through an 8.125 Angstrom internal diameter, rigid, atomistic channel with polar walls in a rigid membrane using explicit ions and SPC/E water. Channel and bath currents were computed from ten 10-ns trajectories for each of 10 different conditions of concentration and applied voltage. An electric field was applied uniformly throughout the system to all mobile atoms. On average, the resultant net electric field falls primarily across the membrane channel, as expected for two conductive baths separated by a membrane capacitance. The channel is rarely occupied by more than one ion. Current-voltage relations are concentration-dependent and superlinear at high concentrations.Comment: Accepted for publication in Biophysical Journa

    Copper Complexes as Influenza Antivirals: Reduced Zebrafish Toxicity

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    Copper complexes have previously been developed to target His37 in influenza M2 and are effective blockers of both the wild type (WT) and the amantadine-resistant M2S31N. Here, we report that the complexes were much less toxic to zebrafish than CuCl2. In addition, we characterized albumin binding, mutagenicity, and virus resistance formation of these metal complexes, and employed steered molecular dynamics simulations to explore whether the complexes would fit in M2. We also examined their anti-viral efficacy in a multi-generation cell culture assay to extend the previous work with an initial-infection assay, discovering that this is complicated by cell culture medium components. The number of copper ions binding to bovine serum albumin (BSA) correlates well with the number of surface histidines and BSA binding affinity is low compared to M2. No mutagenicity of the complexes was observed when compared to sodium azide. After 10 passages of virus in MDCK culture, the EC50 was unchanged for each of the complexes, i.e. resistance did not develop. The simulations revealed that the compounds fit well in the M2 channel, much like amantadine

    Applied field nonequilibrium molecular dynamics simulations of ion exit from a β-barrel model of the L-type calcium channel

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    AbstractWe present results of applied field nonequilibrium molecular dynamics simulations (AF NEMD) of a minimal β-barrel model channel intended to represent an L-type calcium channel that suggests a possible relationship between glutamate side chain conformational changes and ion flux in calcium channels. The β-barrel is used to provide a scaffolding for glutamate side chains and a confinement for electrolyte of dimensions similar to the expected channel structure. It was preloaded with ions to explore relative rates of ion exit for different occupancy configurations. Our simulations with an asymmetrical flexible selectivity filter represented by four glutamate side chains (EEEE), one of which differs in initial dihedrals from the other three, indicate a plausible mechanism for the observed anomalous mole fraction effect seen in calcium channels. Apparent rates of electric field-induced exit from channels preloaded with three Na+ ions are much higher than for channels with one Ca2+ followed by two Na+ ions, consistent with the common notion that Ca2+ block of Na+ current is due to competition between the Ca2+ and Na+ ions for the negatively charged (EEEE) locus. In our model, the Ca2+ ion ligates simultaneously to the four negatively charged glutamate side chains and sterically blocks the permeation pathway. Ca2+-relief of Ca2+-block is suggested by a much higher rate of exit for channels preloaded with three Ca2+ ions than for channels with two Ca2+ ions
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