Sequence-dependent response of DNA to torsional stress: a potential biological regulation mechanism

Abstract

Torsional restraints on DNA change in time and space during the life of the cell and are an integral part of processes such as gene expression, DNA repair and packaging. The mechanical behavior of DNA under torsional stress has been studied on a mesoscopic scale, but little is known concerning its response at the level of individual base pairs and the effects of base pair composition. To answer this question, we have developed a geometrical restraint that can accurately control the total twist of a DNA segment during all-atom molecular dynamics simulations. By applying this restraint to four different DNA oligomers, we are able to show that DNA responds to both under- and overtwisting in a very heterogeneous manner. Certain base pair steps, in specific sequence environments, are able to absorb most of the torsional stress, leaving other steps close to their relaxed conformation. This heterogeneity also affects the local torsional modulus of DNA. These findings suggest that modifying torsional stress on DNA could act as a modulator for protein binding via the heterogeneous changes in local DNA structure.

BZIP Transcription Factors Modulate DNA Supercoiling Transitions

“…steps to torsional stress ( Figure 2). In accordance with our previous studies 8,9 , the TpG and CpA steps of C-TpG-A and T-CpA-G motifs exhibit major torsional flexibility in free DNA, effectively absorbing both negative and positive torsional stress. The two tetranucleotide motifs are symmetrical, each belonging to the MARE-half site.…”

“…1 Computational experiments confirm: DNA responds to torsional stress in a heterogeneous and sequencedependent manner. 8,9 Certain dinucleotide steps, mainly pyrimidine-purine (YpR) but also purine-purine (RpR), in specific sequence environments, absorb a large part of DNA over-and undertwisting, while the rest of the molecule preserves its relaxed B-like conformation. The torsional plasticity of these dinucleotides is founded in the polymorphic nature of the DNA backbone.…”

“…We perform all-atom umbrella sampling simulations using a torsional restraint that controls the total twist of a DNA molecule. 8 The restraint does not restrict any other degrees of freedom of DNA and can be applied to DNA alone and in complex with proteins while running molecular dynamics simulations. We observe that MafB locks the most torsionally flexible dinucleotide steps from oscillating between low-and high-twist substates, through forming specific contacts with the bases.…”

“…of the MARE-half sites. Since the helical parameters shift and twist are structurally coupled via the BI/BII backbone conformational transitions, 12,8,9 the protein-induced negative shift locks the TpG and CpA dinucleotides in a high twist substate. We monitor the evolution of the MafB-DNA contacts network to estimate the structural impact of changing torsional stress on the protein-DNA complex.…”

Sequence-specific dynamics of DNA response elements and their flanking sites regulate the recognition by AP-1 transcription factors

“…Moreover, changes in shift are coupled to changes in twist through DNA backbone BI → BII transitions; 14,48,49 therefore, we also observe an alteration of twist for Yap1-bound DNA. This observation is interesting in the context of DNA supercoiling and its role in eukaryotic transcriptional control.…”