Dataset Information

Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.

ABSTRACT: The recent delivery of a fluorescent quinolizidine-substituted spiropyran, which is able to switch in vivo and bind to guanine quadruplexes (G4) at physiological pH values, urged us to elucidate its molecular switching and binding mechanism. Combining multiscale dynamical studies and accurate quantum chemical calculations, we show that, both in water and in the G4 environment, the switching of the spiropyran ring is not promoted by an initial protonation event-as expected by the effect of low pH solutions-but that the deprotonated merocyanine form is an intermediate of the reaction leading to the protonated open species. Additionally, we investigate the binding of both deprotonated and protonated open forms of merocyanine to c-MYC G4s. Both species bind to G4s albeit with different hydrogen-bond patterns and provide distinct rotamers around the exocyclic double bond of the merocyanine forms. Altogether, our study sheds light on the pharmacophoric points for the binding of these probes to DNA, and thereby, contributes to future developments of new G4 binders of the remarkable family of quinolizidine-substituted spiropyrans.

SUBMITTER: Avagliano D

PROVIDER: S-EPMC7589282 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.

Avagliano Davide D Sánchez-Murcia Pedro A PA González Leticia L

Chemistry (Weinheim an der Bergstrasse, Germany) 20200917 57

The recent delivery of a fluorescent quinolizidine-substituted spiropyran, which is able to switch in vivo and bind to guanine quadruplexes (G4) at physiological pH values, urged us to elucidate its molecular switching and binding mechanism. Combining multiscale dynamical studies and accurate quantum chemical calculations, we show that, both in water and in the G4 environment, the switching of the spiropyran ring is not promoted by an initial protonation event-as expected by the effect of low pH ...[more]

PMID: 32368812

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Project description:This computational study investigates the adsorption of various spiropyran and merocyanine isomers on a NaCl substrate using a combination of density functional theory (DFT) and molecular mechanics (MM) calculations. Four different charge methods were used to determine the partial atomic charges for the adsorbate molecules, including Mulliken population analysis and three electrostatic potential (ESP) methods (Merz-Kollman, ChelpG, and Hu-Lu-Yang), while three different force fields (AMBER 3, CHARMM 27, and MM+) were employed for the MM calculations. The results show that the various DFT charge methods produced similar outcomes for the molecules' partial atomic charges, with some exceptions for individual atoms and methods. Additionally, it was found that the ESP charge methods were more sensitive to the conformer orientation than the Mulliken approach. The adsorption behavior of merocyanine conformers with the central bond in trans orientation (T-conformers) was similar for various configurations, with the molecule adsorbing mostly flat with its aromatic rings almost parallel to the substrate. However, C-conformers (with their central bond in cis orientation) and spiropyran isomers exhibited inconsistent adsorption behavior, mostly because only some of the aromatic rings contributed to the adsorption behavior. Due to additional van der Waals interactions of more aromatic rings, the adsorption energies for T-conformers are consistently 0.2-0.3 eV higher than for C-conformers and for spiropyran. The study found that the adsorption geometries and energies of stable T-conformers were independent of the partial atomic charge scheme and force field used, and C-conformers show parameter-dependent behavior upon adsorption, leading to metastable configurations. These findings indicate viable pathways during the spiropyran-merocyanine isomerization reactions. Therefore, the results provide initial insights into the possibility of switching spiropyran isomers into merocyanine isomers and vice versa after adsorption onto substrates.

Dataset Information

Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.

Publications

Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.

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