292 research outputs found
Structure–activity relationship for extracellular block of K+ channels by tetraalkylammonium ions
AbstractExternal tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions
Tuning ion coordination preferences to enable selective permeation
Potassium (K-) channels catalyze K+ ion permeation across cellular membranes
while simultaneously discriminating their permeation over Na+ ions by more than
a factor of a thousand. Structural studies show bare K+ ions occupying the
narrowest channel regions in a state of high coordination by all 8 surrounding
oxygen ligands from the channel walls. As in most channels, the driving force
for selectivity occurs when one ion is preferentially stabilized or
destabilized by the channel compared to water. In the common view of mechanism,
made vivid by textbook graphics, the driving force for selectivity in K-
channels arises by a fit, whereby the channel induces K+ ions to leave water by
offering an environment like water for K+, in terms of both energy and local
structure. The implication that knowledge of local ion coordination in a liquid
environment translates to design parameters in a protein ion channel, producing
similar energetic stabilities, has gone unchallenged, presumably due in part to
lack of consensus regarding ion coordination structures in liquid water.
Growing evidence that smaller numbers and different arrangements of ligands
coordinate K+ ions in liquid water, however, raises new questions regarding
mechanism: how and why should ion coordination preferences change, and how does
that alter the current notions of ion selectivity? Our studies lead to a new
channelcentric paradigm for the mechanism of K+ ion channel selectivity.
Because the channel environment is not liquid-like, the channel necessarily
induces local structural changes in ion coordination preferences that enable
structural and energetic differentiation between ions.Comment: Main manuscript: 12 pages, 6 figures. Supplementary information: 10
pages, 7 figure
Crossover from Isotropic to Directed Percolation
Directed percolation is one of the generic universality classes for dynamic
processes. We study the crossover from isotropic to directed percolation by
representing the combined problem as a random cluster model, with a parameter
controlling the spontaneous birth of new forest fires. We obtain the exact
crossover exponent at using Coulomb gas methods in 2D.
Isotropic percolation is stable, as is confirmed by numerical finite-size
scaling results. For , the stability seems to change. An intuitive
argument, however, suggests that directed percolation at is unstable and
that the scaling properties of forest fires at intermediate values of are
in the same universality class as isotropic percolation, not only in 2D, but in
all dimensions.Comment: 4 pages, REVTeX, 4 epsf-emedded postscript figure
Extracellular Blockade of K+ Channels by Tea: Results from Molecular Dynamics Simulations of the Kcsa Channel
TEA is a classical blocker of K+ channels. From mutagenesis studies, it has been shown that external blockade by TEA is strongly dependent upon the presence of aromatic residue at Shaker position 449 which is located near the extracellular entrance to the pore (Heginbotham, L., and R. MacKinnon. 1992. Neuron. 8:483–491). The data suggest that TEA interacts simultaneously with the aromatic residues of the four monomers. The determination of the 3-D structure of the KcsA channel using X-ray crystallography (Doyle, D.A., J.M. Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, and R. MacKinnon. 1998. Science. 280:69–77) has raised some issues that remain currently unresolved concerning the interpretation of these observations. In particular, the center of the Tyr82 side chains in KcsA (corresponding to position 449 in Shaker) forms a square of 11.8-Å side, a distance which is too large to allow simultaneous interactions of a TEA molecule with the four aromatic side chains. In this paper, the external blockade by TEA is explored by molecular dynamics simulations of an atomic model of KcsA in an explicit phospholipid bilayer with aqueous salt solution. It is observed, in qualitative accord with the experimental results, that TEA is stable when bound to the external side of the wild-type KcsA channel (with Tyr82), but is unstable when bound to a mutant channel in which the tyrosine residue has been substituted by a threonine. The free energy profile of TEA relative to the pore is calculated using umbrella sampling simulations to characterize quantitatively the extracellular blockade. It is found, in remarkable agreement with the experiment, that the TEA is more stably bound by 2.3 kcal/mol to the channel with four tyrosine residues. In the case of the wild-type KcsA channel, TEA (which has the shape of a flattened oblate spheroid) acts as an ideal plug blocking the pore. In contrast, it is considerably more off-centered and tilted in the case of the mutant channel. The enhanced stability conferred by the tyrosine residues does not arise from Π–cation interactions, but appears to be due to differences in the hydration structure of the TEA. Finally, it is shown that the experimentally observed voltage dependence of TEA block, which is traditionally interpreted in terms of the physical position of the TEA along the axis of the pore, must arise indirectly via coupling with the ions in the pore
Elite opinion and foreign policy in post-communist Russia
Russian elite opinion on matters of foreign policy may be classified as ‘Liberal Westerniser’, ‘Pragmatic Nationalist’ and ‘Fundamentalist Nationalist’, terms that reflect longstanding debates about the country’s relationship with the outside world. An analysis of press
statements and election manifestoes together with a programme of elite interviews between 2004 and 2006 suggests a clustering of opinion on a series of strategic issues. Liberal Westernisers seek the closest possible relationship with Europe, and favour eventual membership of the EU and NATO. Pragmatic Nationalists are more inclined to favour practical co-operation, and do not assume an identity of values or interests with the Western countries. Fundamentalist Nationalists place more emphasis on the other former Soviet republics, and on Asia as much as Europe, and see the West as a threat to Russian values as well as to its state interests. Each of these positions,
in turn, draws on an identifiable set of domestic constituencies: Liberal Westernisers on the promarket political parties, Pragmatic Nationalists on the presidential administration and defence and security ministries, and Fundamentalist Nationalists on the Orthodox Church and Communists
Variational Methods for Biomolecular Modeling
Structure, function and dynamics of many biomolecular systems can be
characterized by the energetic variational principle and the corresponding
systems of partial differential equations (PDEs). This principle allows us to
focus on the identification of essential energetic components, the optimal
parametrization of energies, and the efficient computational implementation of
energy variation or minimization. Given the fact that complex biomolecular
systems are structurally non-uniform and their interactions occur through
contact interfaces, their free energies are associated with various interfaces
as well, such as solute-solvent interface, molecular binding interface, lipid
domain interface, and membrane surfaces. This fact motivates the inclusion of
interface geometry, particular its curvatures, to the parametrization of free
energies. Applications of such interface geometry based energetic variational
principles are illustrated through three concrete topics: the multiscale
modeling of biomolecular electrostatics and solvation that includes the
curvature energy of the molecular surface, the formation of microdomains on
lipid membrane due to the geometric and molecular mechanics at the lipid
interface, and the mean curvature driven protein localization on membrane
surfaces. By further implicitly representing the interface using a phase field
function over the entire domain, one can simulate the dynamics of the interface
and the corresponding energy variation by evolving the phase field function,
achieving significant reduction of the number of degrees of freedom and
computational complexity. Strategies for improving the efficiency of
computational implementations and for extending applications to coarse-graining
or multiscale molecular simulations are outlined.Comment: 36 page
Origins of ion selectivity in potassium channels from the perspective of channel block
Potassium channels play crucial roles in physiology, and one of their more important roles is to repolarize the membrane after an action potential in excitable cells (Hille, 2001). During an action potential, Na+ channels open first and depolarize the cell membrane, which is followed closely by their inactivation and subsequent opening of K+ channels that repolarize the cell membrane by allowing K+ to flow out of the cell. If Na+ were allowed to move through K+ channels, the influx of Na+ would compete with the outflow of K+, and the sharp membrane repolarization would no longer occur. It is then paramount that K+ channels select keenly against Na+ ions
Effect of cholesterol on the dipole potential of lipid membranes
The membrane dipole potential, ψd, is an electrical potential difference with a value typically in the range 150 – 350 mV (positive in the membrane interior) which is located in the lipid headgroup region of the membrane, between the linkage of the hydrocarbon chains to the phospholipid glycerol backbone and the adjacent aqueous solution. At its physiological level in animal plasma membranes (up to 50 mol%), cholesterol makes a significant contribution to ψd of approximately 65 mV; the rest arising from other lipid components of the membrane, in particular phospholipids. Via its effect on ψd, cholesterol may modulate the activity of membrane proteins. This could occur through preferential stabilization of protein conformational states. Based on its effect on ψd, cholesterol would be expected to favour protein conformations associated with a small local hydrophobic membrane thickness. Via its membrane condensing effect, which also produces an increase in ψd, cholesterol could further modulate interactions of polybasic cytoplasmic extensions of membrane proteins, in particular P-type ATPases, with anionic lipid headgroups on the membrane surface, thus leading to enhanced conformational stabilization effects and changes to ion pumping activity.Australian Research Counci
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