Guanine quadruplexes (GQs) play crucial roles in various biological processes, and understanding their folding pathways provides insight into their stability, dynamics, and functions. This knowledge aids in designing therapeutic strategies, as GQs are potential targets for anticancer drugs and other therapeutics. Although experimental and theoretical techniques have provided valuable insights into different stages of the GQ folding, the structural complexity of GQs poses significant challenges, and our understanding remains incomplete. This study introduces a novel computational protocol for folding an entire GQ from single-strand conformation to its native state. By combining two complementary enhanced sampling techniques, we were able to model folding pathways, encompassing a diverse range of intermediates. Although our investigation of the GQ free energy surface (FES) is focused solely on the folding of the all-anti parallel GQ topology, this protocol has the potential to be adapted for the folding of systems with more complex folding landscapes.

Department of Physical Chemistry Faculty of Science Palacký University Olomouc Olomouc Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic

IT4Innovations VŠB Technical University of Ostrava Ostrava Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University Olomouc Olomouc Czech Republic

Scuola Internazionale Superiore di Studi Avanzati SISSA Trieste Italy

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