Computer simulations of nucleosome positioning and allosteric effects in DNA

T. Dršata1 and F. Lankaš1,2

1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague, Czech Republic;

 2Laboratory of Informatics and Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Pragure, Czech Republic

The positioning of a nucleosome with respect to DNA is an important factor influencing the regulation of gene expression. It has been shown that particular sequences, like A-tracts (i.e. AnTn or A2n), may facilitate gene activation by excluding nucleosomes, which can be used to fine tune gene expression [1]. The affinity of a DNA oligomer for formation of a nucleosome is given by its sequence dependent structural and mechanical properties.

These properties also play an important role in DNA-mediated allosteric effects. DNA allostery is a phenomenon analogous to the extensively studied allosteric coupling in proteins. Binding of a small ligand or a protein to the DNA can cause changes in the DNA structure and flexibility that affect the binding affinity of a subsequent ligand. Examples include minor groove binders such as pyrrole-imidazole polyamides [2] or heterocyclic diamidines [3], potential gene expression regulators. However, allosteric coupling between proteins bound to the DNA has also been demonstrated experimentally [4].

A viable approach to probe sequence dependent structural and mechanical properties of  DNA are computer simulations. We employed a coarse-grained model of DNA to investigate unique properties of A-tracts and their implications for the nucleosome formation [5]. The model was further extended to describe DNA-mediated allostery involving minor groove binders [6] and pairs of bound proteins [7]. Parameters of the model were inferred from standard explicit solvent simulations of molecular dynamics.

Our work elucidates the seemingly contradictory experimental stiffness data of A-tracts and exposes the differences in properties of symmetric (AnTn) and asymmetric (A2n) A-tracts, with possible implications for gene expression manipulation. Our extended model predicts structural changes of the DNA upon minor groove ligand binding that are in quantitative agreement with experiment. Furthermore, it provides a mechanistic explanation of the experimentally observed allosteric coupling between proteins bound to DNA.

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5. Dršata, T., Špačková, N., Jurečka, P., Zgarbová, M., Šponer, J. and Lankaš, F., Nucleic Acids Res., 2014, 42, 7383-7394.

6. Dršata, T., Zgarbová, M., Špačková, N., Jurečka, P., Šponer, J. and Lankaš, F., J. Phys. Chem. Lett., 2014, 5, 3831-3835

7. Dršata, T., Zgarbová, M., Jurečka, P., Šponer, J. and Lankaš, F., Biophys. J.,