Atomistic Picture for the Folding Pathway of a Hybrid-1 Type Human Telomeric DNA G-quadruplex

Abstract

In this work we studied the folding process of the hybrid-1 type human telomeric DNA G-quadruplex with solvent and ions explicitly modeled. Enabled by the powerful bias-exchange metadynamics and large-scale conventional molecular dynamic simulations, the free energy landscape of this G-DNA was obtained for the first time and four folding intermediates were identified, including a triplex and a basically formed quadruplex. The simulations also provided atomistic pictures for the structures and cation binding patterns of the intermediates. The results showed that the structure formation and cation binding are cooperative and mutually supporting each other. The syn/anti reorientation dynamics of the intermediates was also investigated. It was found that the nucleotides usually take correct syn/anti configurations when they form native and stable hydrogen bonds with the others, while fluctuating between two configurations when they do not. Misfolded intermediates with wrong syn/anti configurations were observed in the early intermediates but not in the later ones. Based on the simulations, we also discussed the roles of the non-native interactions. Besides, the formation process of the parallel conformation in the first two G-repeats and the associated reversal loop were studied. Based on the above results, we proposed a folding pathway for the hybrid-1 type G-quadruplex with atomistic details, which is new and more complete compared with previous ones. The knowledge gained for this type of G-DNA may provide a general insight for the folding of the other G-quadruplexes.

Insights into Stability and Folding of GNRA and UNCG Tetraloops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics

“…This challenge might be solved by using of biased-exchange metadynamics 55 (BEMD), see, e.g., following ref. 56 studying folding of G-DNA quadruplex using BEMD. Nonetheless, we suggest that even the choice of CVs appears to be more challenging compared to the corresponding simulations of proteins.…”

“…Thus, besides that, we monitored unfolding-refolding events in the WT-MetaD simulations and considered the simulations to be fully converged WT-MetaD only when observing several repetitive unfolding-refolding events and diffusive behavior of the simulations in selected CVs.GAGA TL: Initially, we have attempted a 200-ns-long WT-MetaD simulation of GAGA TL using two CVs, namely H core,2.0 and R core,base (see Methods). Similar choice of CVs was successfully used, e.g., for folding of small beta-hairpin peptide, 39 G-DNA triplex, 54 or G-DNA quadruplex 56. In addition, this choice seems to be logical as the unfolded states of TL hairpins are characterized by an unpaired A-RNA stem region, loss of the TL signature interactions and straightening of the RNA strand 58.…”

The folding of 5′-UTR human G-quadruplexes possessing a long central loop

“…G-quadruplexes are known to be topologically extremely variable, and the folding of the structure is often driven by more complicated pathways which do not necessarily respect a simple two-state equilibrium model between the folded and unfolded state, as was recently demonstrated for the human telomeric DNA sequence (Bian et al 2014). The final topology of the structure is usually influenced by a combination of different intrinsic and extrinsic factors, including the sequence of the molecule itself, the natures and concentrations of any monovalent ions, molecular crowding, the pH, and the temperature, among others.…”

Folding of guanine quadruplex molecules–funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies

“…If such penalty potentials are sufficient to induce an exhaustive exploration of the conformational space, the free energy landscape can then be reconstructed, usually as a function of a few of the biased CVs. BE metadynamics has been used to visualize potential unfolding pathway of a hybrid topology of the human telomeric GQ [70].…”