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New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA

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Abstract

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.

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Acknowledgments

We thank the Natural Science Foundation of China (Grants U0832005, 90813011, 21172272), the International S&T Cooperation Program of China (2010DFA34630), and the Science Foundation of Guangzhou (2009A1-E011-6) for their financial support of this study. The water oxygen density contours were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081).

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  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Jin-Qiang Hou, Shuo-Bin Chen, Jia-Heng Tan, Hai-Bin Luo, Ding Li, Lian-Quan Gu & Zhi-Shu Huang

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  1. Jin-Qiang Hou
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10822_2012_9619_MOESM1_ESM.doc

Figures showing ligand charges calculated with HF/6-31G* basis set and followed by RESP calculation (Figure S1); Time dependence of the RMSD of G-quartet heavy atoms (black) and backbone of G-quadruplex (red) (Figure S2); The planes of the first, second and fourth principal components for all the simulations (Figure S3) (DOC 3456 kb)

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Hou, JQ., Chen, SB., Tan, JH. et al. New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA. J Comput Aided Mol Des 26, 1355–1368 (2012). https://doi.org/10.1007/s10822-012-9619-1

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