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.

Figure 1.

Twist distributions of dinucleotide steps derived from 300 ns unrestrained MD trajectories of the four oligomers.

Figure 2.

PMF with respect to the average change of twist per base pair step with respect to the corresponding value for the relaxed oligomer.

Figure 3.

Twist response to the imposed restraint for the base pair steps constituting the central tetranucleotide of each of the four oligomers, showing average values (points) and standard deviations (vertical bars). In each plot, the black line shows the average twist over the 12-bp steps restrained region that can be compared with the desired twist imposed by our restraint (gray line).

Figure 4.

Changes of twist angles for the restrained segment of each oligomer with respect to their relaxed values as a function of the imposed average twist per base pair (Relative Tw deformation (°) = ^actual − (<Tw>^equilibrated − ΔTw^requested)). The coloring of the dots indicates the imposed twist, red to blue corresponding to the range +5° (overtwisting) to −5° undertwisting with respect to the average base pair step twist of the restrained segments (34.9°).

Figure 5.

Normalized distributions of translational inter-base pair helical variables for the steps most affected by the imposed twist in each oligomer: TpA in ACGT and AGCT, CpG in ACGA and CCGA.

Figure 6.

Normalized distributions of rotational inter-base pair helical variables for the steps most affected by the imposed twist in each oligomer: TpA in ACGT and AGCT, CpG in ACGA and CCGA.