Targeting G-quadruplexes with Organic Dyes: Chelerythrine–DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy

Abstract

The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences—representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences—have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE–DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

“…For example, molecular dynamics (MD) simulations have been employed to study the binding modes and determine the corresponding binding free energies of some representatives of the above mentioned photosensitizer families [ 41 , 42 , 43 , 44 ]. Moreover, MD in conjunction with hybrid quantum mechanics/molecular mechanics (QM/MM) approaches have been applied to unravel in a comprehensive manner the binding modes with DNA and the nature of the excited states that give rise to photochemoterapeutic reactivity of organic photosensitizers, such as acetophenone [ 45 ], palmatine [ 46 ], methylene blue [ 23 , 47 ], Nile red and Nile blue [ 21 ], and chelerythrine [ 48 ]. Although several MD studies have been performed to unveil the energetics of the noncovalent binding process of anthraquinone derivatives with DNA, in particular the intercalation binding mode [ 41 , 44 , 48 , 49 ], to our knowledge a detailed study considering the effect of the DNA surrounding environment on the electronic structure of an anthraquinone derivative has not been performed to this date.…”

“…Moreover, MD in conjunction with hybrid quantum mechanics/molecular mechanics (QM/MM) approaches have been applied to unravel in a comprehensive manner the binding modes with DNA and the nature of the excited states that give rise to photochemoterapeutic reactivity of organic photosensitizers, such as acetophenone [ 45 ], palmatine [ 46 ], methylene blue [ 23 , 47 ], Nile red and Nile blue [ 21 ], and chelerythrine [ 48 ]. Although several MD studies have been performed to unveil the energetics of the noncovalent binding process of anthraquinone derivatives with DNA, in particular the intercalation binding mode [ 41 , 44 , 48 , 49 ], to our knowledge a detailed study considering the effect of the DNA surrounding environment on the electronic structure of an anthraquinone derivative has not been performed to this date. Furthermore, in the optics of tailoring more efficient anthraquinone PS derivatives, in particular molecules presenting moieties that favor specific conformations that enhance charge transfer between the PS and the DNA strand, a good place to start would be to consider the pristine anthraquinone (AQ) molecule and to analyze the nature of its electronic structure right after excitation.…”

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States

“…For example, molecular dynamics (MD) simulations have been employed to study the binding modes and determine the corresponding binding free energies of some representatives of the above mentioned photosensitizer families [34][35][36][37]. Moreover, MD in conjunction with hybrid quantum mechanics/molecular mechanics (QM/MM) approaches have been applied to unravel in a comprehensive manner the binding modes with DNA and the nature of the excited states that give rise to photochemoterapeutic reactivity of organic photosensitizers, such as acetophenone [38], palmatine [39], methylene blue [16,40], Nile red and Nile blue [14], and chelerythrine [41], to cite a few. Although several MD studies have been performed to unveil the energetics of the noncovalent binding process of anthraquinone derivatives with DNA, in particular the intercalation binding mode [34,37,42], to our knowledge a detailed study considering the effect of the DNA surrounding environment on the electronic structure of an anthraquinone derivative has not been performed to this date.…”

Enhanced Rigidity Changes Ultraviolet Absorption: Effect of a Merocyanine Binder on G-Quadruplex Photophysics

“… 21 − 24 There exist calculations of UV/vis spectra of telomeric G4 structures, 23 , 24 but the spectroscopic properties of G4–probe complexes are only used as a G4 diagnostic tool to assess whether the probe binds. 25 Molecular dynamics studies have been carried out with G4 binders 26 − 28 with the aim to monitor the spatiotemporal status of G4s by means of fluorescent probes and shed light into the biological role of these DNA structures. In this Letter, we follow a different approach.…”