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The 3D structures of G-Quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase

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Abstract

The unimolecular G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (G1) and d(GTGGTGGGTGGGTGGGT) (G2) are known as the potent nanomolar HIV-1 integrase inhibitors, thus investigating the 3D structures of the two sequences is significant for structure-based rational anti-HIV drug design. In this research, based on the experimental data of circular dichroism (CD) spectropolarimetry and electrospray ionization mass spectrometry (ESI-MS), the initial models of G1 and G2 were constructed by molecular modeling method. The modeling structures of G1 and G2 are intramolecular parallel-stranded quadruplex conformation with three guanine tetrads. Particularly, the structure of G2 possesses a T loop residue between the first and the second G residues that are the component of two adjacent same-stranded G-tetrad planes. This structure proposed by us has a very novel geometry and is different from all reported G-quadruplexes. The extended (35 ns) molecular dynamic (MD) simulations for the models indicate that the G-quadruplexes maintain their structures very well in aqueous solution whether the existence of K+ or NH +4 in the central channel. Furthermore, we perform 500 ns MD simulations for the models in the gas phase. The results show that all the ion-G-quadruplex complexes are maintained during the whole simulations, despite the large magnitude of phosphate-phosphate repulsions. The gas phase MD simulations provide a good explanation to ESI-MS experiments. Our 3D structures for G1 and G2 will assist in understanding geometric formalism of G-quadruplex folding and may be helpful as a platform for rational anti-HIV drug design.

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Acknowledgments

This work was supported by the National Science Foundation of China (20333050, 20673044), PCSIRT (IRT0625). We would like to thank professor David A. Case et al. for giving us the Amber 10.0 software as a freeware.

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Authors and Affiliations

  1. Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun, 130023, People’s Republic of China

    Ming-Hui Li, Yi-Han Zhou, Quan Luo & Ze-Sheng Li

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  1. Ming-Hui Li
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Correspondence to Ze-Sheng Li.

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Li, MH., Zhou, YH., Luo, Q. et al. The 3D structures of G-Quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase. J Mol Model 16, 645–657 (2010). https://doi.org/10.1007/s00894-009-0592-0

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  • DOI: https://doi.org/10.1007/s00894-009-0592-0

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