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Anomalous versus slowed-down Brownian diffusion in the ligand-binding equilibrium.

ABSTRACT: Measurements of protein motion in living cells and membranes consistently report transient anomalous diffusion (subdiffusion) that converges back to a Brownian motion with reduced diffusion coefficient at long times after the anomalous diffusion regime. Therefore, slowed-down Brownian motion could be considered the macroscopic limit of transient anomalous diffusion. On the other hand, membranes are also heterogeneous media in which Brownian motion may be locally slowed down due to variations in lipid composition. Here, we investigate whether both situations lead to a similar behavior for the reversible ligand-binding reaction in two dimensions. We compare the (long-time) equilibrium properties obtained with transient anomalous diffusion due to obstacle hindrance or power-law-distributed residence times (continuous-time random walks) to those obtained with space-dependent slowed-down Brownian motion. Using theoretical arguments and Monte Carlo simulations, we show that these three scenarios have distinctive effects on the apparent affinity of the reaction. Whereas continuous-time random walks decrease the apparent affinity of the reaction, locally slowed-down Brownian motion and local hindrance by obstacles both improve it. However, only in the case of slowed-down Brownian motion is the affinity maximal when the slowdown is restricted to a subregion of the available space. Hence, even at long times (equilibrium), these processes are different and exhibit irreconcilable behaviors when the area fraction of reduced mobility changes.

SUBMITTER: Soula H

PROVIDER: S-EPMC3824720 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Anomalous versus slowed-down Brownian diffusion in the ligand-binding equilibrium.

Soula Hédi H Caré Bertrand B Beslon Guillaume G Berry Hugues H

Biophysical journal 20131101 9

Measurements of protein motion in living cells and membranes consistently report transient anomalous diffusion (subdiffusion) that converges back to a Brownian motion with reduced diffusion coefficient at long times after the anomalous diffusion regime. Therefore, slowed-down Brownian motion could be considered the macroscopic limit of transient anomalous diffusion. On the other hand, membranes are also heterogeneous media in which Brownian motion may be locally slowed down due to variations in ...[more]

PMID: 24209851

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Project description:Single-particle tracking experiments have measured escape times of DNA-binding species diffusing in living cells: CRISPR-Cas9, TetR, and LacI. The observed distribution is a truncated power law. Working backward from the experimental results, the observed distribution appears inconsistent with a Gaussian distribution of binding energies. Working forward, the observed distribution leads to transient anomalous subdiffusion, in which diffusion is anomalous at short times and normal at long times, here only mildly anomalous. Monte Carlo simulations are used to characterize the time-dependent diffusion coefficient D(t) in terms of the anomalous exponent α, the crossover time tcross, and the limits D(0) and D(∞) and to relate these quantities to the escape time distribution. The simplest interpretations identify the escape time as the actual binding time to DNA or the period of one-dimensional diffusion on DNA in the standard model combining one-dimensional and three-dimensional search, but a more complicated interpretation may be required. The model has several implications for cell biophysics. 1) The initial anomalous regime represents the search of the DNA-binding species for its target DNA sequence. 2) Non-target DNA sites have a significant effect on search kinetics. False positives in bioinformatic searches of the genome are potentially rate-determining in vivo. For simple binding, the search would be speeded if false-positive sequences were eliminated from the genome. 3) Both binding and obstruction affect diffusion. Obstruction ought to be measured directly, using as the primary probe the DNA-binding species with the binding site inactivated and eGFP as a calibration standard among laboratories and cell types. 4) Overexpression of the DNA-binding species reduces anomalous subdiffusion because the deepest binding sites are occupied and unavailable. 5) The model provides a coarse-grained phenomenological description of diffusion of a DNA-binding species, useful in larger-scale modeling of kinetics, FCS, and FRAP.

Dataset Information

Anomalous versus slowed-down Brownian diffusion in the ligand-binding equilibrium.

Publications

Anomalous versus slowed-down Brownian diffusion in the ligand-binding equilibrium.

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