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Investigation on the mechanism for the binding and drug resistance of wild type and mutations of G86 residue in HIV-1 protease complexed with Darunavir by molecular dynamic simulation and free energy calculation

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Abstract

Residue Gly86 is considered as the highly conversed residue in the HIV-1 protease. In our work, the detailed binding free energies for the wild-type (WT) and mutated proteases binding to the TMC-114 are estimated to investigate the protein-inhibitor binding and drug resistance mechanism by molecule dynamic simulations and molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. The binding affinities between the mutants and inhibitor are different than that in the wild-type complex and the major resistance to Darunavir (DRV) of G86A and G86S originate from the electrostatic energy and entropy, respectively. Furthermore, free energy decomposition analysis for the WT and mutated complexes on the basis of per-residue indicates that the mutagenesis influences the energy contribution of the residue located at three regions: active site region (residue 24–32), the flap region, and the region around the mutated residue G86 (residue 79–88), especially the flap region. Finally, further hydrogen bonds and structure analysis are carried out to detect the relationship between the energy and conformation. In all, the G86 mutations change the flap region’s conformation. The experimental results are in good agreement with available results.

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Acknowledgments

This work is supported by Natural Scientific Fund of China (11179035) and 973 fund of Chinese Ministry of Science and Technology (2010CB934504). This paper has been performed partly on the Supercomputing Center of University of Science and Technology of China.

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Authors and Affiliations

  1. National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, 230029, People’s Republic of China

    Dan Li, Ying Zhang & Ju-Guang Han

  2. Shanghai DianJi College, Institute of Applied Mathematics and Physics, Shanghai, 201306, People’s Republic of China

    Run-Ning Zhao

  3. Department of Urology and Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, 230025, China

    Song Fan

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  1. Dan Li
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Correspondence to Song Fan or Ju-Guang Han.

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Li, D., Zhang, Y., Zhao, RN. et al. Investigation on the mechanism for the binding and drug resistance of wild type and mutations of G86 residue in HIV-1 protease complexed with Darunavir by molecular dynamic simulation and free energy calculation. J Mol Model 20, 2122 (2014). https://doi.org/10.1007/s00894-014-2122-y

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