title: Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations.
abstract: DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Stadlbauer
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17 listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Kührová
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17 listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Banáš
authors.affiliation: CEITEC - Central European Institute of Technology, Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic National Center for Biomolecular Research, Faculty of Science, Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Koča
authors.affiliation: Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bussi
authors.affiliation: CEITEC - Central European Institute of Technology, Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Trantírek
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17 listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Otyepka
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic CEITEC - Central European Institute of Technology, Masaryk University, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic sponer@ncbr.muni.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Šponer
mesh_terms: D002412:Cations / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D006801:Humans; D056004:Molecular Dynamics Simulation; D016813:Oxytricha / Q000235:genetics; D016615:Telomere / Q000737:chemistry*
chemical_list: D002412:Cations; D004247:DNA