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Background: Guanine quadruplexes (GQs) play vital roles in many cellularprocesses and are of much interest as drug targets. In contrast to theavailability of many structural studies, there is still limited knowledge on GQfolding.  Scope of review: We review recent molecular dynamics (MD) simulation studiesof the folding of GQs, with an emphasis paid to the human telomeric DNA GQ. Weexplain the basic principles and limitations of all types of MD methods used tostudy unfolding and folding in a way accessible to non-specialists. We discussthe potential role of G-hairpin, G-triplex and alternative GQ intermediates inthe folding process. We argue that, in general, folding of GQs is fundamentallydifferent from funneled folding of small fast-folding proteins, and can be bestdescribed by a kinetic partitioning (KP) mechanism. KP is a competition betweenat least two (but often many) well-separated and structurally differentconformational ensembles.  Major conclusions: The KP mechanism is the only plausible way to explainexperiments reporting long time-scales of GQ folding and the existence oflong-lived sub-states. A significant part of the natural partitioning of thefree energy landscape of GQs comes from the ability of the GQ-forming sequencesto populate a large number of syn-anti patterns in their G-tracts. The extremecomplexity of the KP of GQs typically prevents an appropriate description ofthe folding landscape using just a few order parameters or collectivevariables.  General significance: We reconcile available computational and experimentalstudies of GQ folding and formulate basic principles characterizing GQ foldinglandscapes

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