title: Coarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes.
abstract: 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.
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic , Královopolská 135, 612 65 Brno, Czech Republic.|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.
authors: Petr
authors: P
authors: Stadlbauer
authors: Laboratoire de Biochimie Théorique, IBPC, CNRS UPR9080, Université Sorbonne Paris Cite , Paris Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Liuba
authors: L
authors: Mazzanti
authors: Department of Chemistry, Cambridge University , Lensfield Road, Cambridge CB2 1EW, U.K.
authors: Tristan
authors: T
authors: Cragnolini
authors: Department of Chemistry, Cambridge University , Lensfield Road, Cambridge CB2 1EW, U.K.
authors: David J
authors: DJ
authors: Wales
authors: Laboratoire de Biochimie Théorique, IBPC, CNRS UPR9080, Université Sorbonne Paris Cite , Paris Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Philippe
authors: P
authors: Derreumaux
authors: Laboratoire de Biochimie Théorique, IBPC, CNRS UPR9080, Université Sorbonne Paris Cite , Paris Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Samuela
authors: S
authors: Pasquali
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic , Královopolská 135, 612 65 Brno, Czech Republic.
authors: Jiří
authors: J
authors: Šponer
mesh_terms: D054856:G-Quadruplexes; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D016615:Telomere / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics