4.7 Article

Alanine scanning combined with interaction entropy studying the differences of binding mechanism on HIV-1 and HIV-2 proteases with inhibitor

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 39, Issue 5, Pages 1588-1599

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1734488

Keywords

Molecular dynamics simulations; binding free energy calculation; alanine scanning; interaction entropy; HIV protease

Funding

  1. National Key R&D Program of China [2016YFA0501700]
  2. National Natural Science Foundation of China [11774207, 11574184, 21433004, 91753103]
  3. NYU Global Seed Grant

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In this study, binding free energies between two HIV proteases and inhibitors were calculated using the IE method, revealing common hot-spot residues and differences in residue contributions between HIV-1 and HIV-2, explaining variations in inhibitor potency. The research provides quantitative insights into HIV-inhibitor binding mechanisms and offers theoretical guidance for designing equipotent HIV-1/HIV-2 protease inhibitors.
Quantitative characterization of binding affinity in protein-ligand and residue-ligand is critical for understanding binding mechanisms of protein-ligand and predicting hot-spot residues. In this paper, binding free energies between two HIV (HIV-1 and HIV-2) proteases and four inhibitors are calculated by molecular mechanics/generalized Born surface area (MM/GBSA) combined with the newly developed interaction entropy (IE) approach. The internal dielectric constant is set on the basis of different types of amino acids. The entropy change in protein-ligand binding is computed by IE method which is superior to the traditional normal mode (Nmode) method in the analysis of the ranking of binding free energy, statistical stability and enthalpy-entropy compensation. Importantly, IE method combined with alanine scanning is applied to calculate residue-specific binding free energy. And the calculated total binding free energy using the current method is in excellent with the experimental observed. Our research indicates that HIV-1 and HIV-2 proteases share the common hot-spot residues with ILE50/50' and ILE84/ILE84' which provide the major favorable contribution to the binding of protein and inhibitor in all systems. The predicted hot-spot residues are more in HIV-1 complex than HIV-2 complex and some hot-spot residues contributing to HIV-1 don't play a significant role in HIV-2. To some extent, this explains the reason of decrease in potency inhibitors against HIV-2 compared to HIV-1 protease. The study is expected to understand quantitatively the binding mechanism of HIV-inhibitor and provide important theoretical guidance for the design of equipotent HIV-1/HIV-2 protease inhibitors. Communicated by Ramaswamy H. Sarma

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