Identifying the Molecular Mechanics and Binding Dynamics Characteristics of Potent Inhibitors to HIV-1 Protease

Authors

  • Dechang Li,

    1. Biomechanics and Biomaterials Laboratory, Department of Applied Mechanics, Beijing Institute of Technology, Beijing 100081, China
    2. Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
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  • Ming S. Liu,

    Corresponding author
    1. CSIRO – Mathematics, Informatics and Statistics, Private Bag 33, Clayton South 3169, Vic., Australia
    2. Monash Institute of Medical Research, PO Box 5418, Clayton 3168, Vic., Australia
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  • Baohua Ji,

    Corresponding author
    1. Biomechanics and Biomaterials Laboratory, Department of Applied Mechanics, Beijing Institute of Technology, Beijing 100081, China
    2. Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
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  • Keh-Chih Hwang,

    1. Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
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  • Yonggang Huang

    Corresponding author
    1. Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA
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Corresponding authors: Ming S. Liu,ming.liu@csiro.au; Baohua Ji,bhji@bit.edu.cn; Yonggang Huang,y-huang@northwestern.edu

Abstract

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the primary inhibition targets for chemotherapy of AIDS because of its critical role in the replication cycle of the HIV. In this work, a combinatory coarse-grained and atomistic simulation method was developed for dissecting molecular mechanisms and binding process of inhibitors to the active site of HIV-1 PR, in which 35 typical inhibitors were trialed. We found that the molecular size and stiffness of the inhibitors and the binding energy between the inhibitors and PR play important roles in regulating the binding process. Comparatively, the smaller and more flexible inhibitors have larger binding energy and higher binding rates; they even bind into PR without opening the flaps. In contrast, the larger and stiffer inhibitors have lower binding energy and lower binding rate, and their binding is subjected to the opening and gating of the PR flaps. Furthermore, the components of binding free energy were quantified and analyzed by their dependence on the molecular size, structures, and hydrogen bond networks of inhibitors. Our results also deduce significant dynamics descriptors for determining the quantitative structure and property relationship in potent drug ligands for HIV-1 PR inhibition.

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