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Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir

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Abstract

The molecular mechanisms of HIV drug resistance were studied using molecular dynamics simulations of HIV-1 protease complexes with the clinical inhibitor indinavir. One nanosecond molecular dynamics simulations were run for solvated complexes of indinavir with wild type protease, a control variant and 12 drug resistant mutants. The quality of the simulations was assessed by comparison with crystallographic and inhibition data. Molecular mechanisms that contribute to drug resistance include structural stability and affinity for inhibitor. The mutants showed a range of structural variation from 70 to 140% of the wild type protease. The protease affinity for indinavir was estimated by calculating the averaged molecular mechanics interaction energy. A correlation coefficient of 0.96 was obtained with observed inhibition constants for wild type and four mutants. Based on this good agreement, the trends in binding were predicted for the other mutants and discussed in relation to the clinical data for indinavir resistance.

Figure Poincare map representation for WT protease-indinavir complex. The side chain of Tyr 59 showing the positions of hydrogen atoms.

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Acknowledgements

This work was supported in part by the Georgia Research Alliance and the United States Public Health Service Grants GM62920 and GM065762 (to I.T.W. and R.W.H.).

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Authors and Affiliations

  1. Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA

    Xianfeng Chen & Robert W. Harrison

  2. Department of Computer Science, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA

    Robert W. Harrison

  3. Department of Biology, Georgia State University, P.O. Box 4010, Atlanta, GA 30302-4010, USA

    Irene T. Weber

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  1. Xianfeng Chen
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  2. Irene T. Weber
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  3. Robert W. Harrison
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Correspondence to Irene T. Weber.

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Chen, X., Weber, I.T. & Harrison, R.W. Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir. J Mol Model 10, 373–381 (2004). https://doi.org/10.1007/s00894-004-0205-x

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  • DOI: https://doi.org/10.1007/s00894-004-0205-x

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