Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Sequence Dependence of the ?Kink-and-Slide? Deformations of DNA in Nucleosome. All-atom Simulations of DNA Nonharmonic Behavior
What are the ?rules? guiding sequence-dependent packing of DNA in nucleosomes? This long-standing question still remains in the focus of interest of structural biologists. Traditionally, DNA has been considered as an elastic rod whose bending and twisting deformabilities dictate its wrapping around the histone core. Recently, however, it was found that the lateral displacements of the DNA axis play an important structural role (1) which cannot be ignored when analyzing the sequence-dependent folding of DNA in chromatin. In particular, the Slide displacements occurring at sites of sharp DNA bending toward the minor groove make a significant input in the energy cost of DNA deformations in nucleosome. Using the knowledge-based elastic potentials for DNA (2), Tolstorukov et al. (1) demonstrated that these ?Kink-and-Slide? distortions are highly sequence-specific, the CA:TG and TA dimeric steps being the most easily deformable.
On the other hand, the nucleosome X-ray structure (3) indicates that some DNA deformations may exceed the limits of harmonic behavior. For example, the minor-groove Kinks mentioned above are accompanied by local BI/BII transition in the sugar-phosphate backbone, which suggests a non-parabolic profile of DNA bending energy. Therefore, we have undertaken a more detailed investigation in an all-atom approximation, using DNAminiCarlo software (4) where the rotational and translational parameters of bases serve as independent degrees of freedom.
To this aim, we have analyzed multi-dimensional energy landscapes of several double-stranded DNA hexamers containing various YR and RY steps in the center, e.g. CTTAAG, GAATTC, etc. We compared the optimal conformations of hexamers with the Kink-and-Slide distortions in nucleosome (3), which are dictated by histone arginines penetrating into the minor groove: Roll = ?20° and Slide = 2.5 Å. In addition, we paid attention to the inter-relationships between Roll, Slide and BI/BII conformational state.
First, we confirmed the result obtained earlier (5) that if the unrestrained DNA deformations are allowed, the central TA step bends preferably into the major-groove. If, however, the conformational restraints are imposed on DNA trajectory, and the Kink-and-Slide deformation is considered, the hexamers with the central TA step are the most favorable for the minor-groove kink (compared to other sequences). In other words, the TA step most easily accommodates strong negative Roll with concomitant positive Slide imposed by the histone arginines. We also found that the BI/BII transition facilitates the Kink-and-Slide deformation, especially for hexamers with the pyrimidine-purine YR steps in the center. Overall, the Kink-and-Slide deformation energy of DNA increases in the order TA < CA < CG < GC < AC < AT.
Our results are generally consistent with results of Tolstorukov et al. (1), although there are two notable differences. First, the DNA deformation energy calculated here is significantly lower than the estimates made earlier when the elastic energy functions were applied (1), especially for the purine-pyrimidine steps AT and AC. This is yet another illustration that the Kink-and-Slide deformations represent a nonharmonic (nonlinear) behavior of the duplex. Second, TA is the easiest dimeric step to deform according to our data, while it was the second one based on elastic energy predictions (1). Our new results are in a better agreement with experimental data, because this is the TA step that occurs most frequently in the minor-groove kink positions in the most stable nucleosomes (6-7). Therefore, we expect that the DNA deformation energy evaluated here in an all-atom approximation will help refining the scoring functions (1) for prediction of nucleosome positioning.
References and Footnotes
1 Laboratory of Cell Biology