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.
Highlights
G-quadruplexes (G4) are non-canonical four-stranded structures formed by guanine-rich sequences of nucleic acids, in which sets of four guanine residues associate into planar arrays (G-tetrads) through cyclic Hoogsteen hydrogen bonding [1,2,3]
In the present work, we probe the determinants of the stability of G4 dimers by computing the free energy profiles for all possible π-stacked assemblies formed by the parallel telomeric G-quadruplexes, using explicit-solvent all-atom molecular dynamics simulations with a total simulation time of *100 μs. These calculations correctly reproduce the predominance of the direct 5’-5’ stacking mode over the remaining dimeric forms and show that dimerization equilibrium is governed largely by a competition between the electrostatic repulsion of the sugar-phosphate backbones and favorable counterion binding at the interface between the G4 monomers
A clear preference for the 5-5 mode seen in our simulations, both CHARMM36 and parmbsc1, is fully consistent with the available experimental data
Summary
G-quadruplexes (G4) are non-canonical four-stranded structures formed by guanine-rich sequences of nucleic acids, in which sets of four guanine residues associate into planar arrays (G-tetrads) through cyclic Hoogsteen hydrogen bonding [1,2,3]. Gquadruplexes can fold into a variety of topologies, differing in the relative orientation of the four guanine runs and in the arrangement of loop regions [4, 5]. Using structure-specific antibodies and in-cell NMR, DNA G-quadruplexes have been shown to occur throughout the genome in living cells [10,11,12], with a markedly higher density observed at the telomeric regions (up to 25% of all G4 DNA) [13]. Gquadruplexes are thought to be involved in regulation of DNA replication and transcription, genetic recombination, maintaining chromosome stability, and other fundamental cellular processes. With their unique molecular structure and biological significance, G-quadruplexes attracted much attention as drug-design targets [18]. Since G4 structures have been shown to inhibit, among others, telomerase [19] and HIV integrase [20], there is reason to believe that selective G4-stabilizing ligands could act as anti-cancer or anti-viral agents [21, 22]
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