Computational Probing of the Folding Mechanism of Human Telomeric G‑Quadruplex DNA

The human telomeric (htel) sequences in the terminal
regions of
human telomeres form diverse G-quadruplex (GQ) structures. Despite
much experimental efforts to elucidate the folding pathways of htel
GQ, no comprehensive model of htel GQ folding has been presented.
Here, we describe folding pathways of the htel GQ determined by state-of-the-art
enhanced sampling molecular dynamics simulation at the all-atom level.
Briefly, GQ folding is initiated by the formation of a single-hairpin
and then followed by the formation of double-hairpins, which then
branch via distinct folding pathways to produce different GQ topologies
(antiparallel chair, antiparallel basket, hybrids 1 and 2, and parallel
propeller). In addition to these double-hairpin states, three-triad
and two-tetrad structures in antiparallel backbone alignment serve
as key intermediates that connect the GQ folding and transition between
two different GQs.