| Time: | October 10, 2025, 11:00 a.m. – 11:45 a.m. |
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| Lecturer: | Dr. Deniz Mostarac, University of Edinburgh, United Kingdom |
| Venue: | ICP Seminarraum 1.079 Allmandring 3 70569 Vaihingen |
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Coarse-grained modelling of G-quadruplex multimers
G-quadruplexes (G4s) are non-canonical DNA structures formed by guanine-rich oligonucleotides [1]. They are abundant in higher eukaryotic genomes and particularly concentrated in telomeric regions, constituting up to 25% of all DNA G4s [2]. Single-stranded telomeric overhang sequences (ssTELs) can fold into various multimeric G4 configurations with distinct biological roles and potential as drug targets [3]. G4 DNA regulates transcription, translation, DNA replication, and RNA localization, but its overall functions and those of metabolizing enzymes (e.g., helicases) remain incompletely understood [4]. Most prominently, G4s have been shown to inhibit telomerase and HIV integrase, opening the possibility for G4-stabilizing compounds as anticancer medications [5].
Many ligands have been identified that interact with ssTELs to stabilize G4 monomers [6]. Stabilization of ssTELs in cancer cells has been associated with apoptosis [7]. However, ligand effects on G4 multimers and the mechanisms underlying telomerase inhibition remain unclear. Large-scale, long-timescale computational studies are needed to address critical gaps in understanding G4 behavior in crowded and non-crowded environments. Elucidating the polymeric properties of G4 multimers is essential to uncover relationships between flexibility and biopolymer function.
This contribution presents an in-depth study using molecular dynamics simulations, EspressoMD, and a novel coarse-grained G4 model [8] to access long-timescale bulk simulations of complex systems. We validate the model against in vitro experiments and then extend beyond experimental feasibility to investigate the polymeric properties of long G4 multimers and their modulation by ligands, with and without crowders. Finally, we demonstrate, in silico, a novel class of ligands we call polyligands, which offer new ways to manipulate the properties of G4 multimers.
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[2] S. Kolesnikova, E. Curtis, Molecules, 24, 3074 (2019)
[3] G. Biffi, D. Tannahill, J. McCafferty, S. Balasubramanian, Nature. Chem., 5, 182-186 (2013)
[4] J. Huppert, S. Balasubramanian, Nucleic Acids Research, 35, 406-413 (2006)
[5] A. Zahler, J. Williamson, T. Cech, D. Prescott, Nature, 350, 718-720 (1991)
[6] Q. Li, J. Xiang, Q. Yang, H. Sun, A. Guan, Y. Tang, Nucleic Acids Research, 41, D1115-D1123 (2012)
[7] S. Neidle, Nat. Rev. Chem., 1, 0041 (2017)
[8] D. Mostarac, M. Trapella, L. Bertini, L. Comez, A. Paciaroni, C. De Michele, Biomacromolecules, 26, 3128-3138 (2025)