Structural Studies of Supramolecular G‑Quadruplexes Formed from 8‑Aryl-2′-deoxyguanosine Derivatives

Self-assembly
is a powerful tool for the construction of complex
nanostructures. Despite advances in the field, the development of
precise self-assembled structures remains a challenge. We have shown
that, in the presence of suitably sized cations like K+, 8-aryl-2′-deoxyguanosine (8ArG) derivatives self-assemble
into sets of coaxially stacked planar tetramers, which we term supramolecular
G-quadruplexes (SGQs). Previously, we reported that, when the 8-aryl
group is a phenyl ring with a meta-carbonyl group, the resulting supramolecule
is a hexadecamer, which is remarkably robust as illustrated by its
isostructural assembly in both organic and aqueous environments. We
report here a detailed three-dimensional structure of the SGQs formed
by lipophilic, and hydrophilic, 8ArG derivatives with either 8-(meta-acetylphenyl),
8-(para-acetylphenyl), or 8-(meta-ethoxycarbonylphenyl) groups. The
chirality and close contacts between the subunits impose different
levels of steric and electrostatic constraints on opposite sides of
the tetrads, which determine their preferred relative orientation.
The balance between attractive noncovalent interactions juxtaposed
with repulsive steric and electrostatic interactions explains the
high cooperativity, fidelity, and stability of these SGQs. These structural
studies, together with titration experiments and molecular dynamics
simulations, provide insight into the mechanism of formation of these
SGQs.