Theoretical studies on the molecular basis of HIV-1RT/NNRTIs interactions

Abstract

Molecular dynamics simulations (MD) of the human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complexed with the four non-nucleoside reverse transcriptase inhibitors (NNRTIs): efavirenz (EFV), emivirine (EMV), etravirine (ETV) and nevirapine (NVP), were performed to examine the structures, binding free energies and the importance of water molecules in the binding site. The binding free energy, calculated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), was found to decrease in the following order: EFV ∼ ETV > EMV > NVP. The decrease in stability of the HIV-1 RT/NNRTI complexes is in good agreement with the experimentally derived half maximal inhibitory concentration (IC₅₀) values. The interaction energy of the protein-inhibitor complexes was found to be essentially associated with the cluster of seven hydrophobic residues, L100, V106, Y181, Y188, F227, W229 and P236, and two basic residues, K101 and K103. Moreover, these residues are considered to be the most frequently detected mutated amino acids during treatment by various NNRTIs and therefore, those most likely to have been selected in the population for resistance.

Keywords::

• Molecular dynamics simulation
• reverse transcriptase
• HIV-1
• NNRTIs

Acknowledgements

The authors would like to thank the Computational Chemistry Unit Cell, Faculty of Science, Chulalongkorn University, and the Institute of Theoretical Chemistry, University of Vienna, for providing research facilities, software packages and computing time.

Declaration of interest

This work was supported by the Thailand Research Fund and the National Center for Genetic Engineering and Biotechnology (BIOTEC).