352 research outputs found
Reaction coordinates for the flipping of genetic switches
We present a detailed analysis, based on the Forward Flux Sampling (FFS)
simulation method, of the switching dynamics and stability of two models of
genetic toggle switches, consisting of two mutually-repressing genes encoding
transcription factors (TFs); in one model (the exclusive switch), they mutually
exclude each other's binding, while in the other model (general switch) the two
transcription factors can bind simultaneously to the shared operator region. We
assess the role of two pairs of reactions that influence the stability of these
switches: TF-TF homodimerisation and TF-DNA association/dissociation. We
factorise the flipping rate k into the product of the probability rho(q*) of
finding the system at the dividing surface (separatrix) between the two stable
states, and a kinetic prefactor R. In the case of the exclusive switch, the
rate of TF-operator binding affects both rho(q*) and R, while the rate of TF
dimerisation affects only R. In the case of the general switch both TF-operator
binding and TF dimerisation affect k, R and rho(q*). To elucidate this, we
analyse the transition state ensemble (TSE). For the exclusive switch, varying
the rate of TF-operator binding can drastically change the pathway of
switching, while changing the rate of dimerisation changes the switching rate
without altering the mechanism. The switching pathways of the general switch
are highly robust to changes in the rate constants of both TF-operator and
TF-TF binding, even though these rate constants do affect the flipping rate;
this feature is unique for non-equilibrium systems.Comment: 24 pages, 7 figure
Forward Flux Sampling-type schemes for simulating rare events: Efficiency analysis
We analyse the efficiency of several simulation methods which we have
recently proposed for calculating rate constants for rare events in stochastic
dynamical systems, in or out of equilibrium. We derive analytical expressions
for the computational cost of using these methods, and for the statistical
error in the final estimate of the rate constant, for a given computational
cost. These expressions can be used to determine which method to use for a
given problem, to optimize the choice of parameters, and to evaluate the
significance of the results obtained. We apply the expressions to the
two-dimensional non-equilibrium rare event problem proposed by Maier and Stein.
For this problem, our analysis gives accurate quantitative predictions for the
computational efficiency of the three methods.Comment: 19 pages, 13 figure
Radial Squeezed States and Rydberg Wave Packets
We outline an analytical framework for the treatment of radial Rydberg wave
packets produced by short laser pulses in the absence of external electric and
magnetic fields. Wave packets of this type are localized in the radial
coordinates and have p-state angular distributions. We argue that they can be
described by a particular analytical class of squeezed states, called radial
squeezed states. For hydrogenic Rydberg atoms, we discuss the time evolution of
the corresponding hydrogenic radial squeezed states. They are found to undergo
decoherence and collapse, followed by fractional and full revivals. We also
present their uncertainty product and uncertainty ratio as functions of time.
Our results show that hydrogenic radial squeezed states provide a suitable
analytical description of hydrogenic Rydberg atoms excited by short-pulsed
laser fields.Comment: published in Physical Review
Hydrophobic interactions: an overview
We present an overview of the recent progress that has been made in
understanding the origin of hydrophobic interactions. We discuss the different
character of the solvation behavior of apolar solutes at small and large length
scales. We emphasize that the crossover in the solvation behavior arises from a
collective effect, which means that implicit solvent models should be used with
care. We then discuss a recently developed explicit solvent model, in which the
solvent is not described at the atomic level, but rather at the level of a
density field. The model is based upon a lattice-gas model, which describes
density fluctuations in the solvent at large length scales, and a Gaussian
model, which describes density fluctuations at smaller length scales. By
integrating out the small length scale field, a Hamiltonian is obtained, which
is a function of the binary, large-length scale field only. This makes it
possible to simulate much larger systems than hitherto possible as demonstrated
by the application of the model to the collapse of an ideal hydrophobic
polymer. The results show that the collapse is dominated by the dynamics of the
solvent, in particular the formation of a vapor bubble of critical size.
Implications of these findings to the understanding of pressure denaturation of
proteins are discussed.Comment: 10 pages, 4 figure
Spatio-temporal correlations can drastically change the response of a MAPK pathway
Multisite covalent modification of proteins is omnipresent in eukaryotic
cells. A well-known example is the mitogen-activated protein kinase (MAPK)
cascade, where in each layer of the cascade a protein is phosphorylated at two
sites. It has long been known that the response of a MAPK pathway strongly
depends on whether the enzymes that modify the protein act processively or
distributively: distributive mechanism, in which the enzyme molecules have to
release the substrate molecules in between the modification of the two sites,
can generate an ultrasensitive response and lead to hysteresis and bistability.
We study by Green's Function Reaction Dynamics, a stochastic scheme that makes
it possible to simulate biochemical networks at the particle level and in time
and space, a dual phosphorylation cycle in which the enzymes act according to a
distributive mechanism. We find that the response of this network can differ
dramatically from that predicted by a mean-field analysis based on the chemical
rate equations. In particular, rapid rebindings of the enzyme molecules to the
substrate molecules after modification of the first site can markedly speed up
the response, and lead to loss of ultrasensitivity and bistability. In essence,
rapid enzyme-substrate rebindings can turn a distributive mechanism into a
processive mechanism. We argue that slow ADP release by the enzymes can protect
the system against these rapid rebindings, thus enabling ultrasensitivity and
bistability
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