title: Folding of guanine quadruplex molecules-funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies.
abstract: Guanine quadruplexes (GQs) play vital roles in many cellular processes and are of much interest as drug targets. In contrast to the availability of many structural studies, there is still limited knowledge on GQ folding.
  
  
  
  We review recent molecular dynamics (MD) simulation studies of the folding of GQs, with an emphasis paid to the human telomeric DNA GQ. We explain the basic principles and limitations of all types of MD methods used to study unfolding and folding in a way accessible to non-specialists. We discuss the potential role of G-hairpin, G-triplex and alternative GQ intermediates in the folding process. We argue that, in general, folding of GQs is fundamentally different from funneled folding of small fast-folding proteins, and can be best described by a kinetic partitioning (KP) mechanism. KP is a competition between at least two (but often many) well-separated and structurally different conformational ensembles.
  
  
  
  The KP mechanism is the only plausible way to explain experiments reporting long time-scales of GQ folding and the existence of long-lived sub-states. A significant part of the natural partitioning of the free energy landscape of GQs comes from the ability of the GQ-forming sequences to populate a large number of syn-anti patterns in their G-tracts. The extreme complexity of the KP of GQs typically prevents an appropriate description of the folding landscape using just a few order parameters or collective variables.
  
  
  
  We reconcile available computational and experimental studies of GQ folding and formulate basic principles characterizing GQ folding landscapes. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic; Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic. Electronic address: sponer@ncbr.muni.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Šponer
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: Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic; Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University Olomouc, 17. listopadu 12, 771 46 Olomouc, 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, Palacky University Olomouc, 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, Palacky University Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Banáš
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Barira
authors.initials: B
authors.lastname: Islam
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Shozeb
authors.initials: S
authors.lastname: Haider
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Otyepka
mesh_terms: D020029:Base Pairing; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009691:Nucleic Acid Denaturation; D013329:Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry*
chemical_list: D006147:Guanine; D004247:DNA
keywords: Folding landscape; G-quadruplex; Molecular dynamics; Simulation force fields