The hybrid atomistic structure-based model has been validated to be effective in investigation of G-quadruplex folding.In this study,we performed large-scale conventional all-atom simulations to complement the folding mechanism of human telomeric sequence Hte124 revealed by a multi-basin hybrid atomistic structure-based model.Firstly,the real time-scale of folding rate,which cannot be obtained from the structure-based simulations,was estimated directly by constructing a Markov state model.The results show that Hte124 may fold as fast as on the order of milliseconds when only considering the competition between the hybrid-1 and hybrid-2 G-quadruplex conformations.Secondly,in comparison with the results of structure-based simulations,more metastable states were identified to participate in the formation of hybrid-1 and hybrid-2 conformations.These findings suggest that coupling the hybrid atomistic structure-based model and the conventional all-atom model can provide more insights into the folding dynamics of DNA G-quadruplex.As a result,the multiscale computational framework adopted in this study may be useful to study complex processes of biomolecules involving large conformational changes.