Folding of guanine quadruplex molecules–funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 5; pp. 1246 - 1263
• Main Authors: Šponer, Jiří, Bussi, Giovanni, Stadlbauer, Petr, Kührová, Petra, Banáš, Pavel, Islam, Barira, Haider, Shozeb, Neidle, Stephen, Otyepka, Michal
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2017
• Subjects: Base Pairing; DNA; DNA - chemistry; drugs; Folding landscape; G-quadruplex; G-Quadruplexes; Gibbs free energy; guanine; Guanine - chemistry; Humans; Kinetics; Molecular dynamics; Molecular Dynamics Simulation; Nucleic Acid Denaturation; proteins; Simulation force fields; Structure-Activity Relationship; Telomere - chemistry; telomeres; Molecular dynamics; Folding landscape; Simulation force fields; G-quadruplex
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.12.008

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. •G-quadruplex folding process is an extreme case of kinetic partitioning.•Full G-quadruplex folding landscape is not reducible to a few order parameters.•G-quadruplexes with strand-slippage may be key off-pathway intermediates.•Full description of the quadruplex folding remains beyond the reach of MD methods.•Force fields have troubles to describe propeller loops and stability of GG pairs.