The 3D structures of G-quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase.
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.
Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun, 130023, People's Republic of China.
Ming-Hui
MH
Li
Yi-Han
YH
Zhou
Quan
Q
Luo
Ze-Sheng
ZS
Li
D015195:Drug Design; D054856:G-Quadruplexes; D005740:Gases; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D012996:Solutions; D021241:Spectrometry, Mass, Electrospray Ionization
D005740:Gases; D019428:HIV Integrase Inhibitors; D012996:Solutions