Sequence-dependent DNA deformability studied using molecular dynamics simulations

Abstract

Proteins recognize specific DNA sequences not only through direct contact between amino acids and bases, but also indirectly based on the sequence-dependent conformation and deformability of the DNA (indirect readout). We used molecular dynamics simulations to analyze the sequence-dependent DNA conformations of all 136 possible tetrameric sequences sandwiched between CGCG sequences. The deformability of dimeric steps obtained by the simulations is consistent with that by the crystal structures. The simulation results further showed that the conformation and deformability of the tetramers can highly depend on the flanking base pairs. The conformations of xATx tetramers show the most rigidity and are not affected by the flanking base pairs and the xYRx show by contrast the greatest flexibility and change their conformations depending on the base pairs at both ends, suggesting tetramers with the same central dimer can show different deformabilities. These results suggest that analysis of dimeric steps alone may overlook some conformational features of DNA and provide insight into the mechanism of indirect readout during protein-DNA recognition. Moreover, the sequence dependence of DNA conformation and deformability may be used to estimate the contribution of indirect readout to the specificity of protein-DNA recognition as well as nucleosome positioning and large-scale behavior of nucleic acids.

Figure 1.

Six base-pair step parameters. The parameter values were calculated using the X3DNA software package (29).

Figure 2.

Averaged step parameters for the indicated dimeric steps. The solid and dotted lines denote the averaged values for the MD and crystal structures (32), respectively. Error bars indicate the SD for the MD structures.

Figure 3.

Similarity among tetrameric steps. (a) Similarity among the averaged conformations. (b) Similarity among the correlation matrices. High and low similarities are shown by red and blue colors, respectively.

Figure 3.

Similarity among tetrameric steps. (a) Similarity among the averaged conformations. (b) Similarity among the correlation matrices. High and low similarities are shown by red and blue colors, respectively.

Figure 4.

Deformability of tetrameric steps measured by conformational entropy S_xy. The conformational entropy was calculated as the square root of the eigenvector product of the covariance matrix. Larger values indicate that the tetramers have larger conformational spaces. See Supplementary Data for the enlarged figure and raw values of the deformability.

Figure 5.

Highest correlation coefficients between step i and i + n, where n = 1, 2, 3 or 4, for the most rigid and most flexible tetrameric sequences.

Figure 6.

(a) Nucleosome core structure (31) (PDB: 1kx3) drawn using Pymol software (50). (b) Energy distribution of random DNA sequences threaded on the structure (1k×3). The co-crystallized DNA energy is indicated by an arrow, showing the high fitness of the template structure.