Structure-based simulations complemented by conventional all-atom simulations to provide new insights into the folding dynamics of human telomeric G-quadruplex

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 Htel24 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 Htel24 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.