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.

Automated summary

The hybrid atomistic structure-based model has been shown effective in investigating G-quadruplex folding and complementing the folding mechanism of human telomeric sequence Htel24. Real-time folding rate of Htel24 was estimated using a Markov state model, revealing potential fast folding on the order of milliseconds between hybrid-1 and hybrid-2 G-quadruplex conformations. A comparison with structure-based simulations identified more metastable states participating in the formation of hybrid-1 and hybrid-2 conformations, suggesting that coupling hybrid atomistic structure-based model and conventional all-atom model can provide deeper insights into DNA G-quadruplex folding dynamics. This multiscale computational framework may be valuable for studying complex biomolecular processes with large conformational changes.