Abstract
It is well established that gene regulation can be achieved through activator and repressor proteins that bind to DNA and switch particular genes on or off, and that complex metabolic networks determine the levels of transcription of a given gene at a given time. Using three complementary computational techniques to study the sequence-dependence of DNA denaturation within DNA minicircles, we have observed that whenever the ends of the DNA are constrained, information can be transferred over long distances directly by the transmission of mechanical stress through the DNA itself, without any requirement for external signalling factors. Our models combine atomistic molecular dynamics (MD) with coarse-grained simulations and statistical mechanical calculations to span three distinct spatial resolutions and timescale regimes. While they give a consensus view of the non-locality of sequence-dependent denaturation in highly bent and supercoiled DNA loops, each also reveals a unique aspect of long-range informational transfer that occurs as a result of restraining the DNA within the closed loop of the minicircles.
Highlights
Compartmentalization is well established as a strategy that has evolved to manage the complex environment of the cell.Organelles, vesicles and proteinaceous microcompartments in bacteria all provide physical boundaries that enable multiple metabolic processes to run concurrently and which optimize the speed of transfer of biological information through modified diffusion distances
We show that there are a variety of mechanisms for long-range information transfer and non-locality through mechanical stress in closed DNA loops, which apply more generally whenever DNA is topologically restrained, such as in genomic DNA
SIDD and the coarse-grained oxDNA calculations agree that singlestranded regions occur with highest probability in the centre of AT-rich regions due to the lower thermodynamic stability of AT relative to GC base pairs and the nucleation barrier associated with the loss of base stacking interactions at the interface between ss and dsDNA
Summary
Compartmentalization is well established as a strategy that has evolved to manage the complex environment of the cell.Organelles, vesicles and proteinaceous microcompartments in bacteria all provide physical boundaries that enable multiple metabolic processes to run concurrently and which optimize the speed of transfer of biological information through modified diffusion distances. We have used a combination of statistical physics and multi-scale structural modelling applied to DNA minicircles containing ∼100 base pairs to demonstrate that the mechanics of topologically restrained DNA is determined globally and interactively, not locally. We show that there are a variety of mechanisms for long-range information transfer and non-locality through mechanical stress in closed DNA loops, which apply more generally whenever DNA is topologically restrained, such as in genomic DNA. The focus here is on minicircles because DNA loops of this size permit detailed modelling at a range of structural resolutions (atomistic, single base and using phenomenological models), and reveal the interplay between torsional and bending stress within the duplex, which is representative of the most extreme mechanical distortions experienced by supercoiled DNA
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