Molecular mechanisms behind BRACO19 and human telomeric G-quadruplex interaction

Year: 2024

Authors: Libera V., Fasolato C., Ripanti F., Catalini S., Bertini L., Petrillo C., Schiro G., D’Amico F., Rossi B., Paciaroni A., Comez L.

Autors Affiliation: Univ Perugia, Dept Phys & Geol, Via Alessandro Pascoli, I-06123 Perugia, Italy; Natl Res Council ISC CNR, Inst Complex Syst, Piazzale Aldo Moro 5, I-00185 Rome, Italy; European Lab Nonlinear Spect LENS, Via Nello Carrara 1, I-50019 Sesto Fiorentino, FI, Italy; Natl Inst Opt CNR INO, Natl Res Council, Largo E Fermi 6, I-50125 Florence, Italy; Univ Grenoble Alpes, Inst Biol Struct, CNRS, CEA, F-38044 Grenoble, France; Elettra Sincrotrone Trieste S C p A ss, 14 Km 163,500 Area Sci Pk, I-34149 Trieste, Italy; CNR IOM, Ist Officina Materiali IOM, Via Alessandro Pascoli, I-06123 Perugia, Italy; Marche Polytech Univ, Dept Life & Environm Sci, via Brecce Bianche, I-60131 Ancona, Italy.

Abstract: Human telomeres (HTs) can form DNA G-quadruplex (G4), an attractive target for anticancer and antiviral drugs. HT-G4s exhibit inherent structural polymorphism, posing challenges for understanding their specific recognition by ligands. Here, we aim to explore the impact of different topologies within a small segment of the HT (Tel22) on its interaction with BRACO19, a rationally designed G4 ligand with high quadruplex affinity, already employed in in-vivo treatments. Our multi-technique approach is based on the combined use of a set of contactless spectroscopic tools. Circular dichroism and UV resonance Raman spectroscopy probe ligandinduced conformational changes in the G4 sequence, while UV-visible absorption, coupled with steady-state fluorescence spectroscopy, provides further insights into the electronic features of the complex, exploiting the photoresponsive properties of BRACO19. Overall, we find that modifying the topology of the unbound Tel22 through cations (K + or Na + ), serves as a critical determinant for ligand interactions and binding modes, thus influencing the HT-G4’s assembly capabilities. Furthermore, we show how fluorescence serves as a valuable probe for recognizing cation-driven multimeric structures, which may be present in living organisms, giving rise to pathological forms.

Journal/Review: SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY

Volume: 322      Pages from: 124684-1  to: 124684-10

More Information: The authors acknowledge Elettra Sincrotrone Trieste for providing access to its synchrotron radiation facilities and for financial support (propos al numbers 20200281 and 20190362) . The BL10.2-IUVS beamline scientists are also acknowledged for their kind support during the Raman measurements, and A. Gessini for several technical discussions. We are finally very grateful to J.B. Chaires and J.O. Trent for providing the script to analyze CD spectra.
KeyWords: G-quadruplex; BRACO19; Circular dichroism spectroscopy; Fluorescence spectroscopy; UV-visible absorption spectroscopy; UV resonant Raman spectroscopy
DOI: 10.1016/j.saa.2024.124684

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