New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA

Abstract

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.

Small‐molecule G‐quadruplex interactions: Systematic exploration of conformational space using multiple molecular dynamics

“…The good correspondence between the MD clusters and the experimental NMR structures for RHSP4, suggest that the protocols described here, can reliably reproduce experimental data, at least for conformationally rigid molecules. The well‐documented flexibility of quadruplex loops is shown here to be complex in nature, dependent on ligand, loop number and whether the binding site is 3′ or 5′, further supporting the need to undertake an extended computational approach, such as is described here, if small molecule binding sites are to be fully explored. At present, this approach is computationally expensive, although one can be confident that improved algorithms and hardware will enable the approach to become routine in time.…”

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

“…The calculated and experimental values of the absolute ligand/DNA binding free energy are in good agreement, especially considering the approximation of both the theoretical and experimental model. The application of FM allows overcoming limitations of the previous simulations (42, 69, 70) such as exhaustive exploration of the phase space and convergence of calculation, however conserving the full flexibility of DNA. Taking into account the conformational freedom of DNA is crucial because ligand binding might be affected by specific G4-DNA conformations (70).…”

Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

“…The escape of ions from the quadruplex channel as recorded in tris-H 2 PyP-AQ and tris-H 2 PzP-AQ, which are bound to the parallel quadruplex, has been previously highlighted (Hou et al, 2012). This consequently enhances the instability of G-tetrads as indicated by the low occupancy of corresponding Hoogsteen H-bondings, implying the central role of cation in stabilizing the quartet stems.…”