Acceleration of bursty multiprotein target search kinetics on DNA by colocalisation

Abstract

Proteins are capable of locating specific targets on DNA by employing a facilitated diffusion process with intermittent 1D and 3D search steps. Gene colocalisation and coregulation-i.e. the spatial proximity of two communicating genes-is one factor capable of accelerating the target search process along the DNA. We perform Monte Carlo computer simulations and demonstrate the benefits of gene colocalisation for minimising the search time in a model DNA-protein system. We use a simple diffusion model to mimic the search for targets by proteins, produced initially in bursts of multiple proteins and performing the first-passage search on the DNA chain. The behaviour of the mean first-passage times to the target is studied as a function of distance between the initial position of proteins and the DNA target position, as well as versus the concentration of proteins. We also examine the properties of bursty target search kinetics for varying physical-chemical protein-DNA binding affinity. Our findings underline the relevance of colocalisation of production and binding sites for protein search inside biological cells.

Burst statistics in an early biofilm quorum sensing model: the role of spatial colony-growth heterogeneity

“…Thus, gene expression and molecular signalling processes in cells are typically performed by passive diffusion 79 , as active transport would easily exceed the resources of a cell. The often extremely low concentrations of signalling molecules may be compensated by spatial proximity (geometry-control) 80 between the loci where the molecules are produced and where they are supposed to bind 81–84 . For the QS scenario we here showed that excessive production of AIs may not lead to more reliable signalling and, thus, allows a similar housekeeping economy for the partaking cells.…”

“…Additional important aspects to study include different, potentially anisotropic dispersal, proliferation, and motility strategies of bacterial cells 8 , non-Fickian or anomalous diffusion of AI molecules 84 , as well as the diffusivity of AI molecules depending on local bacteria density (transport channels and porosity of a biofilm) 8,61,63 . Other biologically-relevant aspects should include stimulations of cell mortality (when local cell densities become too high to allow flows of nutrients and oxygen), disposal of poisonous metabolic/waste products, of the history of experiencing cell environments 36 , mimicking heterogeneous micro-scale structure of bacterial biofilms/colonies 9,10 , and QS mechanisms for multiple species of QS-signalling molecules (“interference”) 14 .…”

Structural Basis of Enhanced Facilitated Diffusion of DNA Binding Proteins in Crowded Cellular Milieu

“…Flanking DNA sequence around the target DNA site has also been found to modulate the search process by altering the funnel-shaped protein-DNA binding energy landscape (8). These multifaceted search mechanisms have been captured in vitro via different spectroscopic approaches (9)(10)(11)(12)(13), and also through in silico models and simulations (14)(15)(16)(17)(18)(19)(20)(21)(22)(23) at single molecule level. The in vivo condition is, however, entirely different due to the presence of an astounding concentration (∼100-300 mg/ml) of dissolved macromolecules (24,25).…”

How does supercoiling regulation on a battery of RNA polymerases impact on bacterial transcription bursting?

“…In addition, a general framework of stochastic transcription has been built to address both the uncorrelated transcription events and bursting behaviors [14]. Besides, the bursting transcription is suggested to lead to protein localization to facilitate target search in the transcription regulation, according to another recent modeling work [15].…”