Surface area accessibility and the preferred topology of telomeric DNA quadruplex–ligand complexes

Solvent-accessible surface area calculations have been performed on two human telomeric quadruplex structures, the parallel crystal structure and an (3 + 1) anti-parallel structure determined by NMR methods. The differences in net ligand solvent-accessible surface area (ΔSASA) for four structurally distinct categories of small-molecule ligand have been computed, using docked structures of complexes with both types of quadruplex, as well as the relative contributions of polar and non-polar surface areas. It has been hypothesized that the surface area occupied by the ligand is a determinant of selectivity between different quadruplex topologies, where the ligand maximizes the accessible surface area by contacting all accessible atoms at one end of a quadruplex structure. This has enabled selectivity for a particular ligand to be assessed, for parallel compared an anti-parallel topology. The predictions for the ligands chosen, all of which have their quadruplex topological preferences experimentally determined and reported in the literature, are fully in accord with observation. It is suggested that this approach, which does not depend on energy functions, can be useful in the rational design of topology-specific ligands, especially in the case of polymorphic quadruplexes.

► Determining the preferred topology for human telomeric quadruplex.
► Ligand complexes accessible surface area calculated for ligands bound.
► To different topologies difference in net surface area contacted by ligands.
► Ligand shows topological preferences.
► These are in agreement with experimental data.