69 research outputs found
First-passage time to clear the way for receptor-ligand binding in a crowded environment
Certain biological reactions, such as receptor-ligand binding at cell-cell
interfaces and macromolecules binding to biopolymers, require many smaller
molecules crowding a reaction site to be cleared. Examples include the T cell
interface, a key player in immunological information processing. Diffusion sets
a limit for such cavitation to occur spontaneously, thereby defining a
timescale below which active mechanisms must take over. We consider
independent diffusing particles in a closed domain, containing a sub-region
with particles, on average. We investigate the time until the
sub-region is empty, allowing a subsequent reaction to proceed. The first
passage time is computed using an efficient exact simulation algorithm and an
asymptotic approximation in the limit that cavitation is rare. In this limit,
we find that the mean first passage time is sub-exponential, . For the case of T cell receptors, we find that stochastic
cavitation is exceedingly slow, seconds at physiological densities,
however can be accelerated to occur within 5 second with only a four-fold
dilution
Random intermittent search and the tug-of-war model of motor-driven transport
We formulate the tug-of-war model of microtubule cargo transport by multiple molecular motors as an intermittent random search for a hidden target. A motor-complex consisting of multiple molecular motors with opposing directional preference is modeled using a discrete Markov process. The motors randomly pull each other off of the microtubule so that the state of the motor-complex is determined by the number of bound motors. The tug-of-war model prescribes the state transition rates and corresponding cargo velocities in terms of experimentally measured physical parameters. We add space to the resulting Chapman-Kolmogorov (CK) equation so that we can consider delivery of the cargo to a hidden target somewhere on the microtubule track. Using a quasi-steady state (QSS) reduction technique we calculate analytical approximations of the mean first passage time (MFPT) to find the target. We show that there exists an optimal adenosine triphosphate (ATP)concentration that minimizes the MFPT for two different cases: (i) the motor complex is composed of equal numbers of kinesin motors bound to two different microtubules (symmetric tug-of-war model), and (ii) the motor complex is composed of different numbers of kinesin and dynein motors bound to a single microtubule(asymmetric tug-of-war model)
Metastability in a stochastic neural network modeled as a velocity jump Markov process
One of the major challenges in neuroscience is to determine how noise that is
present at the molecular and cellular levels affects dynamics and information
processing at the macroscopic level of synaptically coupled neuronal
populations. Often noise is incorprated into deterministic network models using
extrinsic noise sources. An alternative approach is to assume that noise arises
intrinsically as a collective population effect, which has led to a master
equation formulation of stochastic neural networks. In this paper we extend the
master equation formulation by introducing a stochastic model of neural
population dynamics in the form of a velocity jump Markov process. The latter
has the advantage of keeping track of synaptic processing as well as spiking
activity, and reduces to the neural master equation in a particular limit. The
population synaptic variables evolve according to piecewise deterministic
dynamics, which depends on population spiking activity. The latter is
characterised by a set of discrete stochastic variables evolving according to a
jump Markov process, with transition rates that depend on the synaptic
variables. We consider the particular problem of rare transitions between
metastable states of a network operating in a bistable regime in the
deterministic limit. Assuming that the synaptic dynamics is much slower than
the transitions between discrete spiking states, we use a WKB approximation and
singular perturbation theory to determine the mean first passage time to cross
the separatrix between the two metastable states. Such an analysis can also be
applied to other velocity jump Markov processes, including stochastic
voltage-gated ion channels and stochastic gene networks
Uniform asymptotic approximation of diffusion to a small target: Generalized reaction models
The diffusion of a reactant to a binding target plays a key role in many biological processes. The reaction radius at which the reactant and target may interact is often a small parameter relative to the diameter of the domain in which the reactant diffuses. We develop uniform in time asymptotic expansions in the reaction radius of the full solution to the corresponding diffusion equations for two separate reactant-target interaction mechanisms: the Doi or volume reactivity model and the Smoluchowski-Collins-Kimball partial-absorption surface reactivity model. In the former, the reactant and target react with a fixed probability per unit time when within a specified separation. In the latter, upon reaching a fixed separation, they probabilistically react or the reactant reflects away from the target. Expansions of the solution to each model are constructed by projecting out the contribution of the first eigenvalue and eigenfunction to the solution of the diffusion equation and then developing matched asymptotic expansions in Laplace-transform space. Our approach offers an equivalent, but alternative, method to the pseudopotential approach we previously employed [Isaacson and Newby, Phys. Rev. E 88, 012820 (2013)PLEEE81539-375510.1103/PhysRevE.88.012820] for the simpler Smoluchowski pure-absorption reaction mechanism. We find that the resulting asymptotic expansions of the diffusion equation solutions are identical with the exception of one parameter: the diffusion-limited reaction rates of the Doi and partial-absorption models. This demonstrates that for biological systems in which the reaction radius is a small parameter, properly calibrated Doi and partial-absorption models may be functionally equivalent
First-Passage Time to Clear the Way for Receptor-Ligand Binding in a Crowded Environment
Certain biological reactions, such as receptor-ligand binding at cell-cell interfaces and macromolecules binding to biopolymers, require many smaller molecules crowding a reaction site to be cleared. Examples include the T-cell interface, a key player in immunological information processing. Diffusion sets a limit for such cavitation to occur spontaneously, thereby defining a time scale below which active mechanisms must take over. We consider N independent diffusing particles in a closed domain, containing a subregion with N_{0} particles, on average. We investigate the time until the subregion is empty, allowing a subsequent reaction to proceed. The first-passage time is computed using an efficient exact simulation algorithm and an asymptotic approximation in the limit that cavitation is rare. In this limit, we find that the mean first-passage time is subexponential, Tβe^{N_{0}}/N_{0}^{2}. For the case of T-cell receptors, we find that stochastic cavitation is exceedingly slow, 10^{9} s at physiological densities; however, it can be accelerated to occur within 5 s with only a fourfold dilution
Extreme first passage times for populations of identical rare events
A collection of identical and independent rare event first passage times is
considered. The problem of finding the fastest out of such events to occur
is called an extreme first passage time. The rare event times are singular and
limit to infinity as a positive parameter scaling the noise magnitude is
reduced to zero. In contrast, previous work has shown that the mean of the
fastest event time goes to zero in the limit of an infinite number of walkers.
The combined limit is studied. In particular, the mean time and the most likely
path taken by the fastest random walker are investigated. Using techniques from
large deviation theory, it is shown that there is a distinguished limit where
the mean time for the fastest walker can take any positive value, depending on
a single proportionality constant. Furthermore, it is shown that the mean time
and most likely path can be approximated using the solution to a variational
problem related to the single-walker rare event
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