G-quadruplexes are the most important noncanonical DNA architectures. Many quadruplex-forming sequences, including the human telomeric sequence d(GGGTTA)n, have been investigated due to their implications in cancer and other diseases, and because of their potential in DNA-based nanotechnology. Despite the availability of atomistic structural studies of folded G-quadruplexes, their folding pathways remain mysterious, and mutually contradictory models of folding coexist in the literature. Recent experiments convincingly demonstrated that G-quadruplex folding often takes days to reach thermodynamic equilibrium. Based on atomistic simulations of diverse classes of intermediates in G-quadruplex folding, we have suggested that the folding is an extremely multipathway process combining a kinetic partitioning mechanism with conformational diffusion. However, complete G-quadruplex folding is far beyond the time scale of atomistic simulations. Here we use high-resolution coarse-grained simulations to investigate potential unfolding intermediates, whose structural dynamics are then further explored with all-atom simulations. This multiscale approach indicates how various pathways are interconnected in a complex network. Spontaneous conversions between different folds are observed. We demonstrate the inability of simple order parameters, such as radius of gyration or the number of native H-bonds, to describe the folding landscape of the G-quadruplexes. Our study also provides information relevant to further development of the coarse-grained force field.

Department of Chemistry Cambridge University Lensfield Road Cambridge CB2 1EW U K

Institute of Biophysics Academy of Sciences of the Czech Republic Královopolská 135 612 65 Brno Czech Republic

Laboratoire de Biochimie Théorique IBPC CNRS UPR9080 Université Sorbonne Paris Cite Paris Diderot 13 rue Pierre et Marie Curie 75005 Paris France

Regional Centre of Advanced Technologies and Materials Departments of Physical Chemistry Faculty of Science Palacký University 17 listopadu 1192 12 771 46 Olomouc Czech Republic

References provided by Crossref.org

Computer Folding of Parallel DNA G-Quadruplex: Hitchhiker's Guide to the Conformational Space

Parallel G-triplexes and G-hairpins as potential transitory ensembles in the folding of parallel-stranded DNA G-Quadruplexes

Structural dynamics of propeller loop: towards folding of RNA G-quadruplex

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview