Atomistic picture for the folding pathway of a hybrid-1 type human telomeric DNA G-quadruplex.

Yunqiang Bian,Jun Wang,Yuebiao Sheng,Wei Wang,Jian Zhang,Cheng Tan,Alexander Donald Mackerell

doi:10.1371/journal.pcbi.1003562

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.

Highlights

G-quadruplexes are high-order DNA or RNA structures formed from guanine-rich sequences, and their building blocks are Gtetrads that arise from Hoogsten hydrogen-bonding between four guanines
Based on the above results we proposed an atomistic picture for the folding process of the hybrid-1 type G-DNA and discussed its relevance to the previous experimental and theoretical results
The free energy landscape and the intermediates The convergence of the bias-exchange metadynamics was tested by monitoring the random walk of the replicas in their collective variable (CV) spaces, the exchange probability as a function of simulation time, and the evolution of FEL during simulation (Figure S3)

Summary

Introduction

G-quadruplexes are high-order DNA or RNA structures formed from guanine-rich sequences, and their building blocks are Gtetrads that arise from Hoogsten hydrogen-bonding between four guanines. G-quadruplexes are attractive drug designing targets for treating cancers and platforms for delivering drugs [4]. Despite of their functional importance, the folding processes by which they achieve the functional structures have not been well understood as that of DNA and RNA duplexes [5,6,7,8,9,10,11,12]. The folding of G-quadruplexes is a difficult problem due to its sensitivity to the terminal nucleotides, the dependence on ion types and concentration, and due to the little known interplay between metal ions and folding dynamics; the syn/anti reorientations of the glycosidic bonds of the nucleotides further complicate the folding process

Methods

Results

Conclusion