Journal of Molecular Modeling

, Volume 16, Issue 4, pp 645–657

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

Original Paper

DOI: 10.1007/s00894-009-0592-0

Cite this article as:
Li, M., Zhou, Y., Luo, Q. et al. J Mol Model (2010) 16: 645. doi:10.1007/s00894-009-0592-0

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 NH4+ 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.

Keywords

GuadruplexMolecular dynamic simulationMolecular modelingPrincipal components analysisStability

Supplementary material

894_2009_592_MOESM1_ESM.doc (629 kb)
ESM 1(DOC 629 kb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ming-Hui Li
    • 1
  • Yi-Han Zhou
    • 1
  • Quan Luo
    • 1
  • Ze-Sheng Li
    • 1
  1. 1.Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and Computational ChemistryJilin UniversityChangchunPeople’s Republic of China