Probing the limits of supramolecular G-quadruplexes using atomistic molecular dynamics simulations

Abstract

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 (2T)-SGQs, while some form dodecamers (3T-SGQs), or hexadecamers (4T-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.

Quantifying and Modulating Protein Encapsulation in Guanosine-Based Supramolecular Particles

“…Earlier, we established that assembling G-derivatives is a crucial step in creating the SHS particles. , Specifically, G-derivatives containing a meta-phenyl carbonyl group attached to the C8 of the guanine moiety form SGQs containing 16 subunits (i.e., hexadecamers). , We have also shown that combining two types of G-derivatives could lead to the formation of heteromeric SGQs whose responsive properties could be modulated . Building on this, we hypothesized that combining varying proportions of 2 with 3 or 4 would enable adjusting the apparent affinity of the resulting SHS particle toward the target protein AVI .…”

Quantifying and modulating protein encapsulation in guanosine-based supramolecular particles

“…10,34 Specifically, G-derivatives containing a meta-phenyl carbonyl group attached to the C8 of the guanine moiety form SGQs containing 16 subunits (i.e., hexadecamers). 19,35 We have also shown that combining two types of G-derivatives could lead to the formation of heteromeric SGQs whose responsive properties could be modulated. 34 Building on this, we hypothesized that combining varying proportions of 2 with 3 or 4 would enable adjusting the apparent affinity of the resulting SHS particle towards the target protein AVI.…”

Quantifying and modulating protein encapsulation in guanosine-based supramolecular particles

“…Our previous research has demonstrated that G-derivatives containing a metaphenylcarbonyl group attached to the C8 of the guanine moiety form hexadecameric SGQs, containing 16 subunits. 33,34 Therefore, we anticipated that combining 2 with 3 or 4 would lead to the formation of similar hexadecameric SGQs. Our hypothesis was supported by the presence of two sets of peaks in the 1 H NMR of homomeric assembly of SGQ2, which are more clearly visible in the signature N1H region (13-11 ppm; see Figure S44B).…”