μABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
Bottom Line: We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature.We confirm that base sequence effects depend strongly not only on the specific base pair step, but also on the specific base pairs that flank each step.By analyzing the conformation of the phosphodiester backbones, it is possible to understand for which sequences these substates will arise, and what impact they will have on specific helical parameters.
Affiliation: Section de Mathématiques, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.Show MeSH
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Mentions: We can now turn to an analysis of DNA backbone parameters and, in particular, to the ϵ (C3′-O3′) and ζ (O3′-P) dihedrals that have already been shown to play an important role in defining B-DNA conformational substates (24,47–49). The reason for this is that backbone dihedrals preferably occupy distinct conformations, gauche+ (g+), gauche− (g–) or trans (t), which represent minima of the corresponding torsional energy. In the case of ϵ and ζ, which lie on the 3′-side of each deoxyribose sugar, transitions tend to be coupled and favor the combinations (ϵ = t)/(ζ = g–), known as BI and characteristic of canonical B-DNA, or (ϵ = g–)/(ζ = t), known as BII. The base stacking preferences of a given dinucleotide step can favor a BI/BII transition, leading to a discrete conformational substate reflected not only in the phosphodiester backbone, but also in the local helical parameters. In fact, not only the nature of the dinucleotide steps, but also the nature of their flanking sequences strongly influence the proportion of neighboring BI and BII conformations. This is illustrated in Figure 5 (see also Supplementary Figure S7 for a more detailed view of the BI/BII distributions). As we can see, the percentage occurrence of BII states is very variable. Thus, YR steps (irrespective of the flanking sequence) strongly disfavor BI–BII transitions and the BII population rarely exceeds 20% in either strand. This is also the case for AT steps and for the Crick strand of all RR steps. In contrast, the Watson strand of RR steps, and both strands of GC and GT steps show highly variable BII percentages that are strongly influenced by the flanking base pairs and, in particular, by the base pair on the 5′-side. Looking at the color-coded results in Figure 5, we can see that for each of the seven RR and RY steps, a 5′-flanking pyrimidine (blue Y..R and orange Y..Y families) favors relatively high BII percentages, while low percentages occur with a 5′-purine (R..R and R..Y shown in red and green, respectively). Note that this is also true for the Crick strand of GT steps, where the R..R flanking sequence (red) on the Watson strand corresponds to Y..Y on the Crick strand.
Affiliation: Section de Mathématiques, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.