Abstract
Torsional stress on DNA, introduced by molecular motors, constitutes an important regulatory mechanism of transcriptional control. Torsional stress can modulate specific binding of transcription factors to DNA and introduce local conformational changes that facilitate the opening of promoters and nucleosome remodelling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total twist of a DNA fragment, we address the impact of torsional stress on DNA complexation with a human BZIP transcription factor, MafB. We gradually over- and underwind DNA alone and in complex with MafB by 0.5° per dinucleotide step, starting from the relaxed state to a maximum of 5° per dinucleotide step, monitoring the evolution of the protein-DNA contacts at different degrees of torsional strain. Our computations show that MafB changes the DNA sequence-specific response to torsional stress. The dinucleotide steps that are susceptible to absorbing most of the torsional stress become more torsionally rigid, as they are involved in protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stress-induced DNA deformation, but mostly maintains the specific contacts with DNA. This results in a significant asymmetric increase of free energy of DNA twisting transitions, relative to free DNA, where overtwisting is more energetically unfavourable. Our data suggest that specifically bound BZIP factors could act as torsional stress insulators, modulating the propagation of torsional stress along the chromatin fibre, which might promote cooperative binding of collaborative DNA-binding factors.
Highlights
Torsional restraints on DNA, referred to as DNA supercoiling, constantly change during the life of the cell, and regulate transcriptional control on many levels[1,2,3,4,5]
The crystal structure of the MafB-DNA complex shows no major DNA deformation, which justifies the usage of B-form DNA as a reference state and, more importantly, allows us to decouple the impact of writhing and twisting on mechanisms of protein-DNA recognition and complex stability under supercoiling transitions
Maf response element (MARE)-region, we gradually increase or decrease the total twist by 0.5°/b.p., starting from the relaxed state to a maximum of ± 5°/b.p, which corresponds to a change in supercoiling density of ± 0.15, to obtain the potential of mean force (PMF) of DNA twisting free energy as a function of average b.p. twist
Summary
Torsional restraints on DNA, referred to as DNA supercoiling, constantly change during the life of the cell, and regulate transcriptional control on many levels[1,2,3,4,5]. The twist transitions are coupled with significant changes in other helical parameters, such as shift and slide We hypothesize that these dinucleotide steps are potential ’hot spots’ for transcriptional control, as they can regulate supercoiling transitions, the deformability of DNA, and specific binding by transcription factors. Our computations show that MafB changes the sequence-specific response of DNA to torsional stress by making the b.p. steps that are expected to absorb the majority of the applied torsional stress rigid. This results in an asymmetric free energy profile, where overwinding becomes significantly more unfavourable. Our data suggest that bound BZIP factors could act as torsional stress insulators, modulating the propagation of torsional stress along the chromatin fiber, which might promote cooperative binding of collaborative DNA-binding factors and regulate the firing potential of the occupied promoters
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