E. Abad

Reaction-subdiffusion and reaction-superdiffusion equations for evanescent particles performing continuous-time random walks

Starting from a continuous-time random-walk (CTRW) model of particles that may evanesce as they walk, our goal is to arrive at macroscopic integrodifferential equations for the probability density for a particle to be found at point r at time t given that it started its walk from r_{0} at time t=0 . The passage from the CTRW to an integrodifferential equation is well understood when the particles are not evanescent. Depending on the distribution of stepping times and distances, one arrives at standard macroscopic equations that may be normal (diffusion) or anomalous (subdiffusion and/or superdiffusion). The macroscopic description becomes considerably more complicated and not particularly intuitive if the particles can die during their walk. While such equations have been derived for specific cases, e.g., for location-independent exponential evanescence, we present a more general derivation valid under less stringent constraints than those found in the current literature.

Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels.

Potassium ion channels form pores in cell membranes, allowing potassium ions through while preventing the passage of sodium ions. Despite numerous high-resolution structures, it is not yet possible to relate their structure to their single molecule function other than at a qualitative level. Over the past decade, there has been a concerted effort using molecular dynamics to capture the thermodynamics and kinetics of conduction by calculating potentials of mean force (PMF). These can be used, in conjunction with the electro-diffusion theory, to predict the conductance of a specific ion channel. Here, we calculate seven independent PMFs, thereby studying the differences between two potassium ion channels, the effect of the CHARMM CMAP forcefield correction, and the sensitivity and reproducibility of the method. Thermodynamically stable ion–water configurations of the selectivity filter can be identified from all the free energy landscapes, but the heights of the kinetic barriers for potassium ions to move through the selectivity filter are, in nearly all cases, too high to predict conductances in line with experiment. This implies it is not currently feasible to predict the conductance of potassium ion channels, but other simpler channels may be more tractable.

Exploration and Trapping of Mortal Random Walkers

Exploration and trapping properties of random walkers that may evanesce at any time as they walk have seen very little treatment in the literature, and yet a finite lifetime is a frequent occurrence, and its effects on a number of random walk properties may be profound. For instance, whereas the average number of distinct sites visited by an immortal walker grows with time without bound, that of a mortal walker may, depending on dimensionality and rate of evanescence, remain finite or keep growing with the passage of time. This number can in turn be used to calculate other classic quantities such as the survival probability of a target surrounded by diffusing traps. If the traps are immortal, the survival probability will vanish with increasing time. However, if the traps are evanescent, the target may be spared a certain death. We analytically calculate a number of basic and broadly used quantities for evanescent random walkers.

Survival probability of an immobile target in a sea of evanescent diffusive or subdiffusive traps: a fractional equation approach.

We calculate the survival probability of an immobile target surrounded by a sea of uncorrelated diffusive or subdiffusive evanescent traps (i.e., traps that disappear in the course of their motion). Our calculation is based on a fractional reaction-subdiffusion equation derived from a continuous time random walk model of the system. Contrary to an earlier method valid only in one dimension (d=1), the equation is applicable in any Euclidean dimension d and elucidates the interplay between anomalous subdiffusive transport, the irreversible evanescence reaction, and the dimension in which both the traps and the target are embedded. Explicit results for the survival probability of the target are obtained for a density ρ(t) of traps which decays (i) exponentially and (ii) as a power law. In the former case, the target has a finite asymptotic survival probability in all integer dimensions, whereas in the latter case there are several regimes where the values of the decay exponent for ρ(t) and the anomalous diffusion exponent of the traps determine whether or not the target has a chance of eternal survival in one, two, and three dimensions.

Continuous-time random-walk model for anomalous diffusion in expanding media

Expanding media are typical in many different fields, e.g., in biology and cosmology. In general, a medium expansion (contraction) brings about dramatic changes in the behavior of diffusive transport properties such as the set of positional moments and the Greens function. Here, we focus on the characterization of such effects when the diffusion process is described by the continuous-time random-walk (CTRW) model. As is well known, when the medium is static this model yields anomalous diffusion for a proper choice of the probability density function (pdf) for the jump length and the waiting time, but the behavior may change drastically if a medium expansion is superimposed on the intrinsic random motion of the diffusing particle. For the case where the jump length and the waiting time pdfs are long-tailed, we derive a general bifractional diffusion equation which reduces to a normal diffusion equation in the appropriate limit. We then study some particular cases of interest, including Lévy flights and subdiffusive CTRWs. In the former case, we find an analytical exact solution for the Greens function (propagator). When the expansion is sufficiently fast, the contribution of the diffusive transport becomes irrelevant at long times and the propagator tends to a stationary profile in the comoving reference frame. In contrast, for a contracting medium a competition between the spreading effect of diffusion and the concentrating effect of contraction arises. In the specific case of a subdiffusive CTRW in an exponentially contracting medium, the latter effect prevails for sufficiently long times, and all the particles are eventually localized at a single point in physical space. This big crunch effect, totally absent in the case of normal diffusion, stems from inefficient particle spreading due to subdiffusion. We also derive a hierarchy of differential equations for the moments of the transport process described by the subdiffusive CTRW model in an expanding medium. From this hierarchy, the full time evolution of the second-order moment is obtained for some specific types of expansion. In the case of an exponential expansion, exact recurrence relations for the Laplace-transformed moments are obtained, whence the long-time behavior of moments of arbitrary order is subsequently inferred. Our analytical and numerical results for both Lévy flights and subdiffusive CTRWs confirm the intuitive expectation that the medium expansion hinders the mixing of diffusive particles occupying separate regions. In the case of Lévy flights, we quantify this effect by means of the so-called Lévy horizon.

Evanescent continuous-time random walks.

We study how an evanescence process affects the number of distinct sites visited by a continuous-time random walker in one dimension. We distinguish two very different cases, namely, when evanescence can only occur concurrently with a jump, and when evanescence can occur at any time. The first is characteristic of trapping processes on a lattice, whereas the second is associated with spontaneous death processes such as radioactive decay. In both of these situations we consider three different forms of the waiting time distribution between jumps, namely, exponential, long tailed, and ultraslow.

Diffusion in an expanding medium: Fokker-Planck equation, Green's function and first-passage properties

We present a classical, mesoscopic derivation of the Fokker-Planck equation for diffusion in an expanding medium. To this end, we take a conveniently generalized Chapman-Kolmogorov equation as the starting point. We obtain an analytical expression for the Greens function (propagator) and investigate both analytically and numerically how this function and the associated moments behave. We also study first-passage properties in expanding hyperspherical geometries. We show that in all cases the behavior is determined to a great extent by the so-called Brownian conformal time τ(t), which we define via the relation τ[over ̇]=1/a^{2}, where a(t) is the expansion scale factor. If the medium expansion is driven by a power law [a(t)∝t^{γ} with γ>0], then we find interesting crossover effects in the mixing effectiveness of the diffusion process when the characteristic exponent γ is varied. Crossover effects are also found at the level of the survival probability and of the moments of the first passage-time distribution with two different regimes separated by the critical value γ=1/2. The case of an exponential scale factor is analyzed separately both for expanding and contracting media. In the latter situation, a stationary probability distribution arises in the long-time limit.

Optimal search strategies of space-time coupled random walkers with finite lifetimes

We present a simple paradigm for detection of an immobile target by a space-time coupled random walker with a finite lifetime. The motion of the walker is characterized by linear displacements at a fixed speed and exponentially distributed duration, interrupted by random changes in the direction of motion and resumption of motion in the new direction with the same speed. We call these walkers mortal creepers. A mortal creeper may die at any time during its motion according to an exponential decay law characterized by a finite mean death rate ω(m). While still alive, the creeper has a finite mean frequency ω of change of the direction of motion. In particular, we consider the efficiency of the target search process, characterized by the probability that the creeper will eventually detect the target. Analytic results confirmed by numerical results show that there is an ω(m)-dependent optimal frequency ω=ω(opt) that maximizes the probability of eventual target detection. We work primarily in one-dimensional (d=1) domains and examine the role of initial conditions and of finite domain sizes. Numerical results in d=2 domains confirm the existence of an optimal frequency of change of direction, thereby suggesting that the observed effects are robust to changes in dimensionality. In the d=1 case, explicit expressions for the probability of target detection in the long time limit are given. In the case of an infinite domain, we compute the detection probability for arbitrary times and study its early- and late-time behavior. We further consider the survival probability of the target in the presence of many independent creepers beginning their motion at the same location and at the same time. We also consider a version of the standard target problem in which many creepers start at random locations at the same time.

A reaction–subdiffusion model of fluorescence recovery after photobleaching (FRAP)

Anomalous diffusion, in particular subdiffusion, is frequently invoked as a mechanism of motion in dense biological media, and may have a significant impact on the kinetics of binding/unbinding events at the cellular level. In this work we incorporate anomalous diffusion in a previously developed model for FRAP experiments. Our particular implementation of subdiffusive transport is based on a continuous time random walk (CTRW) description of the motion of fluorescent particles, as CTRWs lend themselves particularly well to the inclusion of binding/unbinding events. In order to model switching between bound and unbound states of fluorescent subdiffusive particles, we derive a fractional reaction-subdiffusion equation of rather general applicability. Using suitable initial and boundary conditions, this equation is then incorporated in the model describing two-dimensional kinetics of FRAP experiments. We find that this model can be used to obtain excellent fits to experimental data. Moreover, recovery curves corresponding to different radii of the circular bleach spot can be fitted by a single set of parameters. While not enough evidence has been collected to claim with certainty that CTRW is the underlying transport mechanism in FRAP experiments, the compatibility of our results with experimental data fuels the discussion as to whether normal diffusion or anomalous diffusion is the appropriate model, and as to whether anomalous diffusion effects are important to fully understand the outcomes of FRAP experiments. On a more technical side, we derive explicit analytic solutions of our model in certain limits.

Detailed examination of a single conduction event in a potassium channel

Although extensively studied, it has proved difficult to describe in detail how potassium ion channels conduct cations and water. We present a computational study that, by using stratified umbrella sampling, examines nearly an entire conduction event of the Kv1.2/2.1 paddle chimera and thereby identifies the expected stable configurations of ions and waters in the selectivity filter of the channel. We describe in detail the motions of the ions and waters during a conduction event, focusing on how waters and ions enter the filter, the rotation of water molecules inside the filter, and how potassium ions are coordinated as they move from a water to a protein environment. Finally, we analyze the small conformational changes undergone by the protein, showing that the stable configurations are most similar to the experimental crystal structure.