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Register a new userQuantitative approach to facilitated diffusion with intersegmental jumping
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We study the impact of DNA coiling on the search rate of proteins moving along the DNA contour interspersed by three-dimensional (3D) bulk excursions. When the DNA is coiled proteins performing short 3D hops along a DNA segment can be captured by foreign DNA segments that have looped back close to the original segment. These intersegmental jumps are shown to enhance the search rate for a specific site on the DNA by lowering the tendency to resample previously visited sites on the DNA. The model developed here offers a quantitative description of recent single molecule experiments on facilitated diffusion of restriction enzymes EcoRV.
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We present a theoretical model of facilitated diffusion of proteins in the cell nucleus. This model, which takes into account the successive binding/unbinding events of proteins to DNA, relies on a fractal description of the chromatin which has been recently evidenced experimentally. Facilitated diffusion is shown quantitatively to be favorable for a fast localization of a target locus by a transcription factor, and even to enable the minimization of the search time by tuning the affinity of the transcription factor with DNA. This study shows the robustness of the facilitated diffusion mechanism, invoked so far only for linear conformations of DNA.
While seemingly straightforward in principle, the reliable estimation of rate constants is seldom easy in practice. Numerous issues, such as the complication of poor reaction coordinates, cause obvious approaches to yield unreliable estimates. When a reliable order parameter is available, the reactive flux theory of Chandler allows the rate constant to be extracted from the plateau region of an appropriate reactive flux function. However, when applied to real data from single-molecule experiments or molecular dynamics simulations, the rate can sometimes be difficult to extract due to the numerical differentiation of a noisy empirical correlation function or difficulty in locating the plateau region at low sampling frequencies. We present a modified version of this theory which does not require numerical derivatives, allowing rate constants to be robustly estimated from the time-correlation function directly. We compare these approaches using single-molecule force spectroscopy measurements of an RNA hairpin.
Dynamics of a particle diffusing in a confinement can be seen a sequence of bulk-diffusion-mediated hops on the confinement surface. Here, we investigate the surface hopping propagator that describes the position of the diffusing particle after a prescribed number of encounters with that surface. This quantity plays the central role in diffusion-influenced reactions and determines their most common characteristics such as the propagator, the first-passage time distribution, and the reaction rate. We derive explicit formulas for the surface hopping propagator and related quantities for several Euclidean domains: half-space, circular annuli, circular cylinders, and spherical shells. These results provide the theoretical ground for studying diffusion-mediated surface phenomena. The behavior of the surface hopping propagator is investigated for both immortal and mortal particles.
In living cells, proteins combine 3D bulk diffusion and 1D sliding along the DNA to reach a target faster. This process is known as facilitated diffusion, and we investigate its dynamics in the physiologically relevant case of confined DNA. The confining geometry and DNA elasticity are key parameters: we find that facilitated diffusion is most efficient inside an isotropic volume, and on a flexible polymer. By considering the typical copy numbers of proteins in vivo, we show that the speedup due to sliding becomes insensitive to fine tuning of parameters, rendering facilitated diffusion a robust mechanism to speed up intracellular diffusion-limited reactions. The parameter range we focus on is relevant for in vitro systems and for facilitated diffusion on yeast chromatin.
We describe a 3D percolation-type approach to modeling of the processes of aging and certain other properties of tissues analyzed as systems consisting of interacting cells. Lattice sites are designated as regular (healthy) cells, senescent cells, or vacancies left by dead (apoptotic) cells. The system is then studied dynamically with the ongoing processes including regular cell dividing to fill vacant sites, healthy cells becoming senescent or dying, and senescent cells dying. Statistical-mechanics description can provide patterns of time dependence and snapshots of morphological system properties. The developed theoretical modeling approach is found not only to corroborate recent experimental findings that inhibition of senescence can lead to extended lifespan, but also to confirm that, unlike 2D, in 3D senescent cells can contribute to tissues connectivity/mechanical stability. The latter effect occurs by senescent cells forming the second infinite cluster in the regime when the regular (healthy) cells infinite cluster still exits.
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