Computational understanding and experimental characterization of twice-as-smart quadruplex ligands as chemical sensors of bacterial nucleotide second messengers

Abstract

A twice-as-smart ligand is a small molecule that experiences a structural switch upon interaction with its target (i.e., smart ligand) that concomitantly triggers its fluorescence (i.e., smart probe). Prototypes of twice-as-smart ligands were recently developed to track and label G-quadruplexes: these higher-order nucleic acid structures originate in the assembly of four guanine(G)-rich DNA or RNA strands, whose stability is imparted by the formation and the self-assembly of G-quartets. The first prototypes of twice-as-smart quadruplex ligands were designed to exploit the self-association of quartets, being themselves synthetic G-quartets. While their quadruplex recognition capability has been thoroughly documented, some doubts remain about the precise photophysical mechanism that underlies their peculiar spectroscopic properties. Here, we uncovered this mechanism via complete theoretical calculations. Collected information was then used to develop a novel application of twice-as-smart ligands, as efficient chemical sensors of bacterial signaling pathways via the fluorescent detection of naturally occurring extracellular quadruplexes formed by cyclic dimeric guanosine monophosphate (c-di-GMP).

Applications of guanine quartets in nanotechnology and chemical biology

“…10a). PyroTASQ has been described as a 'twiceassmart' quadruplex ligand 144,145 (Fig. 10a), referring to the fact that it is both a smart quadruplex ligand and a smart, turnon fluorescent probe.…”

Topology‐Selective, Fluorescent “Light‐Up” Probes for G‐Quadruplex DNA Based on Photoinduced Electron Transfer

“…Since intramolecular movements of the probe may also be restricted by events other than binding to the DNA target (e.g., in a viscous microenvironment or upon binding to proteins), leading to a false positive “light‐up” output, probes based on other photophysical mechanisms are highly desired. Along these lines, “smart” fluorescence probes, such as PyroTASQ or coumarin–NDI dyads, which operate through substantial conformational changes upon binding to a G‐quadruplex target, hold a particular promise. In the absence of the substrate, the fluorescence of these probes is quenched due to photoinduced electron transfer (PET) or formation of a non‐fluorescent intramolecular charge‐transfer complex between the fluorophore and a G‐quadruplex‐recognizing moiety (e.g., a G4 ligand, or a self‐assembling G‐quartet in PyroTASQ).…”

Hydrogen-Bonded Rosettes of Aminotriazines for Selective-Ion Recognition

“…Thus, by manipulating and tuning intermolecular forces, chemists could master the controlled design of new materials. This is why the physicochemical information about structural issues and interaction properties, which can be obtained by theoretical calculations, constitutes a valuable background for experimentalists. , …”

“…This is why the physicochemical information about structural issues and interaction properties, which can be obtained by theoretical calculations, constitutes a valuable background for experimentalists. 4,5 An emerging topic in the field of supramolecular chemistry is the use of cyclic rosette complexes 6−9 to build large structures. In this context, 1,3,5-triazine-2,4,6-triamine or melamine (M), which is also very well-known for its uses in the plastic industry, 10 has been considered a very versatile building block for creating a great diversity of sophisticated functional materials.…”