Probing the Limits of Supramolecular G-Quadruplexes Using Atomistic Molecular Dynamics Simulations.

Guanosine and related derivatives self-assemble in the presence of cations like potassium into supramolecular G-quadruplexes (SGQs), where four guanine moieties form planar tetrads (T) that coaxially stack into columnar aggregates with broad size distributions. However, SGQs made from 8-aryl-2'-deoxyguanosine derivatives (8ArGs), form mostly octamers, or two-tetrad (T)-SGQs, while some form dodecamers (T-SGQs), or hexadecamers (T-SGQs), and none reported to date form higher assemblies. A theoretical model that addresses the configurational space available for the multiple pathways available for 8ArGs to self-assemble into SGQs is used to frame a series of molecular dynamics simulations (MDS) with selected SGQs. Some key insights from this work include: (a) The predicted entropic costs are not significantly higher for SGQs with more subunits due to their hierarchical assembly pathways; (b) The multiple isomeric SGQs vary in the interfacial contacts between consecutive tetrads, due to their two distinct sides (head, h; tail, t), with the MDS supporting the predicted order of stability of hh > ht > tt for octamers. (c) Such order also applies to dodecamers and hexadecamers, but with context-dependent exceptions due to strong allosteric effects. (d) The main factor disfavoring the tt interface is the repulsive dipolar interactions between the O4' from ribose moieties on adjacent tetrads. (e) SGQs with 5 or more tetrads are disfavored because the attractive interactions are not large or strong enough to overcome the many repulsive forces resulting from the addition of further tetrads. We expect these findings provide some guidelines to enable the further development of SGQs into functional materials.