  Background: 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.
  Scope of review: 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.
  Major conclusions: 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.
  General significance: We reconcile available computational and experimental
studies of GQ folding and formulate basic principles characterizing GQ folding
landscapes
