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.
Highlights
Guanine quadruplexes (G4s) are non-canonical secondary structures that can be adopted by particular guanine-rich sequences.[1]
We investigated the two possible reaction mechanisms leading to the formation of QMCH from Quinolizidine-substituted spiropyrans (QSP)
The reaction mechanism was investigated by using steered quantum mechanical (QM)/MM molecular dynamics (MD) simulations together with two-dimensional umbrella sampling (2D-US) calculations, both in explicit water solution and bound to c-MYC G4
Summary
Guanine quadruplexes (G4s) are non-canonical secondary structures that can be adopted by particular guanine-rich sequences.[1] They are constituted by stacked guanine tetrads (Gtetrads), formed by four guanine bases interacting with each other through Hoogsteen hydrogen bonding, and chelating a central metal cation.
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