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We study transitions of diffusing particles between the left and right ends of expanding and narrowing conical tubes. In an expanding tube, such transitions occur faster than in the narrowing tube of the same length and radius variation rate. This happens because the entropy potential pushes the particle towards the wide tube end, thus accelerating the transitions in the expanding tube and slowing them down in the narrowing tube. To gain deeper insight into how the transitions occur, we divide each trajectory into the direct-transit and looping segments. The former is the final part of the trajectory, where the particle starting from the left tube end goes to the right end without returning to the left one. The rest of the trajectory is the looping segment, where the particle, starting from the left tube end, returns to this end again and again until the direct transition happens. Our focus is on the durations of the two segments and their sum, which is the duration of the particle first passage between the left and right ends of the tube. We approach the problem using the one-dimensional description of the particle diffusion along the tube axis in terms of the modified Fick-Jacobs equation. This allows us to derive analytical expressions for the Laplace transforms of the probability densities of the firstpassage, direct-transit, and looping times, which we use to find the mean values of these random variables. Our results show that the direct transits are independent of the entropy potential and occur as in free diffusion. However, this "free diffusion" occurs with the effective diffusivity entering the modified Fick-Jacobs equation, which is smaller than the particle diffusivity in a cylindrical tube. This is the only way how the varying tube geometry manifests itself in the direct transits. Since direct-transit times are direction-independent, the difference in the first-passage times in the tubes of the two types is due to the difference in the durations of the looping segments in the expanding and narrowing tubes. Obtained analytical results are supported by three-dimensional Brownian dynamics simulations. [ABSTRACT FROM AUTHOR]

Recent experiments with single biological nanopores, as well as single-molecule fluorescence spectroscopy and pulling studies of protein and nucleic acid folding raised a number of questions that stimulated theoretical and computational investigations of barrier crossing dynamics. The present paper addresses a closely related problem focusing on trajectories of Brownian particles that escape from a cylindrical trap in the presence of a force F parallel to the cylinder axis. To gain new insights into the escape dynamics, we analyze the "fine structure" of these trajectories. Specifically, we divide trajectories into two segments: a looping segment, when a particle unsuccessfully tries to escape returning to the trap bottom again and again, and a direct-transit segment, when it finally escapes moving without touching the bottom. Analytical expressions are derived for the Laplace transforms of the probability densities of the durations of the two segments. These expressions are used to find the mean looping and direct-transit times as functions of the biasing force F. It turns out that the forcedependences of the two mean times are qualitatively different. The mean looping time monotonically increases as F decreases, approaching exponential F-dependence at large negative forces pushing the particle towards the trap bottom. In contrast to this intuitively appealing behavior, the mean directtransit time shows rather counterintuitive behavior: it decreases as the force magnitude, |F|, increases independently of whether the force pushes the particles to the trap bottom or to the exit from the trap, having a maximum at F = 0. [ABSTRACT FROM AUTHOR]

Ligand- or voltage-driven stochastic gating--the structural rearrangements by which the channel switches between its open and closed states--is a fundamental property of biological membrane channels. Gating underlies the channel's ability to respond to different stimuli and, therefore, to be functionally regulated by the changing environment. The accepted understanding of the gating effect on the solute flux through the channel is that the mean flux is the product of the flux through the open channel and the probability of finding the channel in the open state. Here, using a diffusion model of channel-facilitated transport, we show that this is true only when the gating is much slower than the dynamics of solute translocation through the channel. If this condition breaks, the mean flux could differ from this simple estimate by orders of magnitude. [ABSTRACT FROM AUTHOR]

Bacillus anthracis secretes three polypeptides: protective antigen (PA), lethal factor (LF), and edema factor (EF), which interact at the surface of mammalian cells to form toxic complexes. LF and EF are enzymes that target substrates within the cytosol; PA provides a heptameric pore to facilitate LF and EF transport into the cytosol. Other than administration of antibiotics shortly after exposure, there is currently no approved effective treatment for inhalational anthrax. Here we demonstrate an approach to disabling the toxin: high-affinity blockage of the PA pore by a rationally designed low-molecular weight compound that prevents LF and EF entry into cells. Guided by the sevenfold symmetry and predominantly negative charge of the PA pore, we synthesized small cyclic molecules of sevenfold symmetry, [beta]-cyclodextrins chemically modified to add seven positive charges. By channel reconstitution and high-resolution conductance recording, we show that per-6-(3-aminopropylthio)-[beta]-cyclodextrin interacts strongly with the PA pore lumen, blocking PA-induced transport at subnanomolar concentrations (in 0.1 M KCI). The compound protected RAW 264.7 mouse macrophages from cytotoxicity of anthrax lethal toxin (= PA + LF). More importantly, it completely protected the highly susceptible Fischer F344 rats from lethal toxin. We anticipate that this approach will serve as the basis for a structure-directed drug discovery program to find new and effective treatments for anthrax. infectious diseases | membrane transport | modified cyclodextrins

Author(s): Sanjay A. Desai (corresponding author) [1, 2]; Sergey M. Bezrukov [3]; Joshua Zimmerberg [2] Growth of the malaria parasite in human red blood cells (RBCs) is accompanied by an [...]

This paper deals with diffusion of point particles in linearly corrugated two-dimensional channels. Such geometry allows one to obtain an approximate analytical expression that gives the particle effective diffusivity as a function of the geometric parameters of the channel. To establish its accuracy and the range of applicability, the expression is tested against Brownian dynamics simulation results. The test shows that the expression works very well for long channel periods, but fails when the period is not long enough compared to the minimum width of the channel. Tofix this deficiency, we propose a simple empirical correction to the analytical expression. The resulting corrected expression for the effective diffusivity is in excellent agreement with the simulation results for all values of the channel period. [ABSTRACT FROM AUTHOR]

Antibiotic novobiocin is capable of generating cation channels in lipid bilayers and increases salt taste response in rats through regulation of amiloxide-sensitive sodium channels. Single fibers of the rat chorda tympani nerve aid the examination of the role of novobiocin in salt taste transduction. Novobiocin increases the responses of N-type fiber to 100 mM NaCl but does not influence the response of E-type fibers to either 100 mM KCl or 100 mM NaCl.

Axial diffusion in a two-dimensional channel of smoothly varying geometry can be approximately described as one-dimensional diffusion in the entropy potential with position-dependent effective diffusivity by means of the modified Fick-Jacobs equation. In this paper, Brownian dynamics simulations are used to study the range of applicability of such a description, as well as the accuracy of the expressions for the effective diffusivity proposed by different researchers. [ABSTRACT FROM AUTHOR]

This paper is devoted to bulk-mediated surface diffusion of a particle which can diffuse both on a flat surface and in the bulk layer above the surface. It is assumed that the particle is on the surface initially (at t = 0) and at time t, while in between it may escape from the surface and come back any number of times. We propose a new approach to the problem, which reduces its solution to that of a two-state problem of the particle transitions between the surface and the bulk layer, focusing on the cumulative residence times spent by the particle in the two states. These times are random variables, the sum of which is equal to the total observation time t. The advantage of the proposed approach is that it allows for a simple exact analytical solution for the double Laplace transform of the conditional probability density of the cumulative residence time spent on the surface by the particle observed for time t. This solution is used to find the Laplace transform of the particle mean square displacement and to analyze the peculiarities of its time behavior over the entire range of time. We also establish a relation between the double Laplace transform of the conditional probability density and the Fourier-Laplace transform of the particle propagator over the surface. The proposed approach treats the cases of both finite and infinite bulk layer thicknesses (where bulk-mediated surface diffusion is normal and anomalous at asymptotically long times, respectively) on equal footing. [ABSTRACT FROM AUTHOR]

In this paper, we study biased diffusion of point Brownian particles in a three-dimensional comb-like structure formed by a main cylindrical tube with identical periodic cylindrical dead ends. It is assumed that the dead ends are thin cylinders whose radius is much smaller than both the radius of the main tube and the distance between neighboring dead ends. It is also assumed that in the main tube, the particle, in addition to its regular diffusion, moves with a uniform constant drift velocity. For such a system, we develop a formalism that allows us to derive analytical expressions for the Laplace transforms of the first two moments of the particle displacement along the main tube axis. Inverting these Laplace transforms numerically, one can find the time dependences of the two moments for arbitrary values of both the drift velocity and the dead-end length, including the limiting case of infinitely long dead ends, where the unbiased diffusion becomes anomalous at sufficiently long times. The expressions for the Laplace transforms are used to find the effective drift velocity and diffusivity of the particle as functions of its drift velocity in the main tube and the tube geometric parameters. As might be expected from common-sense arguments, the effective drift velocity monotonically decreases from the initial drift velocity to zero as the dead-end length increases from zero to infinity. The effective diffusivity is a more complex, non-monotonic function of the dead-end length. As this length increases from zero to infinity, the effective diffusivity first decreases, reaches a minimum, and then increases approaching a plateau value which is proportional to the square of the particle drift velocity in the main tube. [ABSTRACT FROM AUTHOR]