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Why do G-quadruplexes dimerize through the 5’-ends? Driving forces for G4 DNA dimerization examined in atomic detail
Abstract
G-quadruplexes (G4) are secondary structures formed by guanine-rich nucleic acid sequences and shown to exist in living cells where they participate in regulation of gene expression and chromosome maintenance. G-quadruplexes with solvent-exposed guanine tetrads show the tendency to associate together through cofacial stacking, which may be important for packaging of G4-forming sequences and allows for the design of higher-order G4 DNA structures. To understand the molecular driving forces for G4 association, here, we study the binding interaction between two parallel-stranded G-quadruplexes using all-atom molecular dynamics simulations. The predicted dimerization free energies show that direct binding through the 5’-G-tetrads is the most preferred of all possible end-to-end stacking orientations, consistently with all available experimental data. Decomposition of dimerization enthalpies in combination with simulations at varying ionic strength further indicate that the observed orientational preferences arise from a fine balance between the electrostatic repulsion of the sugar-phosphate backbones and favorable counterion binding at the dimeric interface. We also demonstrate how these molecular-scale findings can be used to devise means of controlling G4 dimerization equilibrium, e.g., by altering salt concentration and using G4-targeted ligands.
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- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1371/journal.pcbi.1007383
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
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PLoS Computational Biology
no. 15,
ISSN: 1553-7358 - Language:
- English
- Publication year:
- 2019
- Bibliographic description:
- Kogut M., Kleist C., Czub J.: Why do G-quadruplexes dimerize through the 5’-ends? Driving forces for G4 DNA dimerization examined in atomic detail// PLoS Computational Biology. -Vol. 15, iss. 9 (2019), s.e1007383-
- DOI:
- Digital Object Identifier (open in new tab) 10.1371/journal.pcbi.1007383
- Verified by:
- Gdańsk University of Technology
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