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 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ion channels are proteins with a hole down their middle that control a vast range of biological function in health and disease. Selectivity is an important biological function determined by the open channel, which does not change conformation on the biological time scale. The challenge is to predict the function-the current of ions of different types and concentrations through a variety of channels-from structure, given fundamental physical laws. Walls of ion channels, like active sites of enzymes, often contain several fixed charges. Those fixed charges demand counter ions nearby, and the density of those counter ions is very high, greater than 5 molar, because of the tiny volumes of the channel's pore. Physical chemists can now calculate the free energy per mole of salt solutions (e.g. the activity coefficient) from infinite dilution to saturation, even in ionic melts. Such calculations of a model of the L-type calcium channel show that the large energies needed to crowd charges into the channel can account for the substantial selectivity and complex properties found experimentally. The properties of such crowded charge are likely to be an important determinant of the properties of proteins in general because channels are nearly enzymes.
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PMID:Proteins, channels and crowded ions. 1264 87

We present results of applied field nonequilibrium molecular dynamics simulations (AF NEMD) of a minimal beta-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 beta-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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PMID:Applied field nonequilibrium molecular dynamics simulations of ion exit from a beta-barrel model of the L-type calcium channel. 1523 53

Biological ion channels are proteins that passively conduct ions across membranes that are otherwise impermeable to ions. Here, we present a model of ion permeation and selectivity through a single, open ryanodine receptor (RyR) ion channel. Combining recent mutation data with electrodiffusion of finite-sized ions, the model reproduces the current/voltage curves of cardiac RyR (RyR2) in KCl, LiCl, NaCl, RbCl, CsCl, CaCl(2), MgCl(2), and their mixtures over large concentrations and applied voltage ranges. It also reproduces the reduced K(+) conductances and Ca(2+) selectivity of two skeletal muscle RyR (RyR1) mutants (D4899N and E4900Q). The model suggests that the selectivity filter of RyR contains the negatively charged residue D4899 that dominates the permeation and selectivity properties and gives RyR a DDDD locus similar to the EEEE locus of the L-type calcium channel. In contrast to previously applied barrier models, the current model describes RyR as a multi-ion channel with approximately three monovalent cations in the selectivity filter at all times. Reasons for the contradicting occupancy predictions are discussed. In addition, the model predicted an anomalous mole fraction effect for Na(+)/Cs(+) mixtures, which was later verified by experiment. Combining these results, the binding selectivity of RyR appears to be driven by the same charge/space competition mechanism of other highly charged channels.
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PMID:(De)constructing the ryanodine receptor: modeling ion permeation and selectivity of the calcium release channel. 1685 78

The cause of the anomalous mole fraction effect (AMFE) in calcium-selective ion channels is studied. An AMFE occurs when the conductance through a channel is lower in a mixture of salts than in the pure salts at the same concentration. The textbook interpretation of the AMFE is that multiple ions move through the pore in coordinated, single-file motion. Instead of this, we find that at its most basic level an AMFE reflects a channel's preferential binding selectivity for one ion species over another. The AMFE is explained by considering the charged and uncharged regions of the pore as electrical resistors in series: the AMFE is produced by these regions of high and low ion concentration changing differently with mole fraction due to the preferential ion selectivity. This is demonstrated with simulations of a model L-type calcium channel and a mathematical analysis of a simplistic point-charge model. The particle simulations reproduce the experimental data of two L-type channel AMFEs. Conditions under which an AMFE may be found experimentally are discussed. The resistors-in-series model provides a fundamentally different explanation of the AMFE than the traditional theory and does not require single filing, multiple occupancy, or momentum-correlated ion motion.
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PMID:The anomalous mole fraction effect in calcium channels: a measure of preferential selectivity. 1851 79