Tuning supramolecular G-quadruplexes with mono- and divalent cations

Abstract

Supramolecular G-quadruplexes (SGQs) are formed via the cation promoted self-assembly of guanine derivatives into stacks of planar hydrogen-bonded tetramers. Here, we present results on the formation of SGQs made from the 8-(m-acetylphenyl)-2′-deoxyguanosine (mAGi) derivative in the presence of various mono- and divalent cations. NMR and HR ESI-MS data indicate that varying the cation can efficiently tune the molecularity, the fidelity and stability (thermal and kinetic) of the resulting SGQs. The results show that, parallel to the previously reported potassium-templated hexadecamer (mAGi16·3K+), Na+, Rb+ and NH4+ also promote the formation of similar supramolecules with high fidelity and molecularity. In contrast, the divalent cations Pb2+, Sr2+ and Ba2+ template the formation of octamers (mAGi8), with the latter two inducing higher thermal stabilities. Molecular dynamics simulations for the hexadecamers containing monovalent cations enabled critical insights that help explain the experimental observations.

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

“…Experimentally, however, we have only identified one type of dodecamer in solution. 18, 21–22, 37, 39–40 Such experimental evidence also strongly suggests that the observed 3 T-SGQ results from the stacking of a third tetrad on a pre-existing D 4 -symmetric 2 T-SGQ. Therefore, we can deduce that the dodecamer formed must have at least one homomeric interface ( hh or tt ), which were the ones selected for further MDS studies (Scheme 1).…”

“…This is energetically costly because of its stabilizing effect due to the ion dipole interactions with the O6 of the guanine moiety. 37, 53 Consequently, an empty assembly should result in greater electrostatic repulsion among the carbonyls aligned at the central cavity of the tetrad resulting in significantly less stable SGQs. Although a number of computational studies have suggested that empty tetrads could be stabilized by - interactions and bifurcated H-bonds, 54–55 the tt 2 T-SGQ ( n T-SGQ: 2 , 3 ) show none of those interactions.…”

“…While we anticipate these results to be broadly general to a wide variety of SGQs made from 8ArGs, there are several outstanding questions pertaining to derivatives lacking the meta-acetylphenyl moiety. For example, we reported the propensity of a 8-(3-pyridyl)-G derivative to form dodecameric SGQs (3T–SGQs) with high fidelity, 18, 21–22, 37, 39–40 because attractive dipole-dipole interactions were enough to stabilize the supramolecular state up to that molecularity, yet, not enough to sustain a stable 4T–SGQ. But, what about other moieties and functionalities?…”

“…20, 22 Furthermore, although not common, we have also observed instances where an ht interface was formed. 37 Based on these observations we assigned values (in arbitrary units) to the three possible interfaces as follows: hh = +2; ht / th = +1; tt = −2. We hypothesized that the first two must be primarily attractive in nature (thus the positive value), with the hh being more favorable than the ht .…”

“…Furthermore, while oligonucleotide based G-quadruplexes (OGQs) have been extensively studied by MDS, 23–33 including their complexes with small molecule ligands, 34–36 there have been fewer MDS studies with SGQs. 22, 37 …”