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.

A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome

“…Thus, AT and TA dinucleotides mark linker/nucleosome borders to a greater degree than found by chance, but not all or even most nucleosomes are marked in such a way. It may be relevant that TA dinucleotides impart more flexibility into DNA, and AT imparts more rigidity, than other dinucleotides (Packer et al 2000;Fujii et al 2007). Such dinucleotides, when present at selective nucleosome borders, might influence nucleosome positioning.…”

Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation

“…Overall, the employment of force field and molecular dynamics approaches appears to provide a better representation of the experimental data to when compared to the static description provided by hybrid QM/MM approaches when compared to a static description. The flexibility and deformability of native DNA has been extensively studied, 16,25,46,49 and it is well established that both features are sequence-dependent, with base composition and the presence of specific sequences substantially contributing to the malleability of the double helix. 16,50 In the present work, the different conformations that DNA can adopt were evaluated by measuring relevant base pair parameters during our simulations.…”

“…The flexibility and deformability of native DNA has been extensively studied, 16,25,46,49 and it is well established that both features are sequence-dependent, with base composition and the presence of specific sequences substantially contributing to the malleability of the double helix. 16,50 In the present work, the different conformations that DNA can adopt were evaluated by measuring relevant base pair parameters during our simulations. Previous work has shown that the AA/TT and GA/TC steps are considered to be the ones with less variability.…”

“…Moreover, the binding of proteins to DNA is entirely dependent on its deformability, in that conformational changes and the sequence-dependent twist are essential for the sequence-specific recognition and binding of DNA by several proteins. 16 A common challenge when trying to model such conformational diversity is the lack of force field parameters for modified nucleotides that are compatible with generally used biomolecular force fields. For this reason, the number of molecular dynamics (MD) studies with modified DNA is limited.…”

Activation of the Carbon Concentrating Mechanism by CO2 Deprivation Coincides with Massive Transcriptional Restructuring in Chlamydomonas reinhardtii

“…In the human genome, 19.4 CA repeats occur per mega base pair, representing the most common simple-sequence repeat motif (Waterston et al, 2002). Among all dinucleotides, the structure of CA dinucleotides are the most stable regardless of their environment, and the stability of the DNA structure enhances the stability of the chromatin as well (Fujii et al, 2007). This stable chromatin structure allows the binding of numerous transcriptional activators and splicing regulators.…”