57,628 research outputs found
Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups
he design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups
Interplay between R513 methylation and S516 phosphorylation of the cardiac voltage-gated sodium channel
Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, Naᵥ1.5. We show that Naᵥ1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S516 phosphorylation blocks R513 methylation. Naᵥ1.5 p.G514C, associated to cardiac conduction disease, abrogates R513 methylation, while leaving S516 phosphorylation rate unchanged. This is the first report of methylation–phosphorylation cross-talk of a cardiac ion channel
Charge fluctuations and boundary conditions of biological ion channels:effect on the ionic transition rate
A self-consistent solution is derived for the Poisson-Nernst-Planck (PNP) equation, valid both inside a biological ion channel and in the adjacent bulk fluid. An iterative procedure is used to match the two solutions together at the channel mouth. Charge fluctuations at the mouth are modeled as shot noise flipping the height of the potential barrier at the selectivity site. The resultant estimates of the conductivity of the ion channel are in good agreement with Gramicidin experimental measurements and they reproduce the observed current saturation with increasing concentration
Beam loading in the nonlinear regime of plasma-based acceleration
A theory that describes how to load negative charge into a nonlinear,
three-dimensional plasma wakefield is presented. In this regime, a laser or an
electron beam blows out the plasma electrons and creates a nearly spherical ion
channel, which is modified by the presence of the beam load. Analytical
solutions for the fields and the shape of the ion channel are derived. It is
shown that very high beam-loading efficiency can be achieved, while the energy
spread of the bunch is conserved. The theoretical results are verified with the
Particle-In-Cell code OSIRIS.Comment: 5 pages, 2 figures, to appear in Physical Review Letter
Fractional diffusion modeling of ion channel gating
An anomalous diffusion model for ion channel gating is put forward. This
scheme is able to describe non-exponential, power-law like distributions of
residence time intervals in several types of ion channels. Our method presents
a generalization of the discrete diffusion model by Millhauser, Salpeter and
Oswald [Proc. Natl. Acad. Sci. USA 85, 1503 (1988)] to the case of a
continuous, anomalous slow conformational diffusion. The corresponding
generalization is derived from a continuous time random walk composed of
nearest neighbor jumps which in the scaling limit results in a fractional
diffusion equation. The studied model contains three parameters only: the mean
residence time, a characteristic time of conformational diffusion, and the
index of subdiffusion. A tractable analytical expression for the characteristic
function of the residence time distribution is obtained. In the limiting case
of normal diffusion, our prior findings [Proc. Natl. Acad. Sci. USA 99, 3552
(2002)] are reproduced. Depending on the chosen parameters, the fractional
diffusion model exhibits a very rich behavior of the residence time
distribution with different characteristic time-regimes. Moreover, the
corresponding autocorrelation function of conductance fluctuations displays
nontrivial features. Our theoretical model is in good agreement with
experimental data for large conductance potassium ion channels
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