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    Ligand Binding Pathways and Conformational Transitions of the HIV Protease

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    Issue Date
    2018-03-06
    Author
    Miao, Yinglong
    Walker, Ross C.
    McCammon, J. Andrew
    Chang, Chia-en A.
    Publisher
    Biochemistry
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein–drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500–2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ~5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug–receptor interactions for the HIV protease and by extension many other target proteins.
    URI
    http://hdl.handle.net/1808/26429
    DOI
    https://doi.org/10.1021/acs.biochem.7b01248
    Collections
    • Molecular Biosciences Scholarly Works [582]
    Citation
    Miao, Y., Huang, Y. M. M., Walker, R. C., McCammon, J. A., & Chang, C. E. A. (2018). Ligand binding pathways and conformational transitions of the HIV protease. Biochemistry, 57(9), 1533-1541.

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    785-864-8983
    KU Libraries
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    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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