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Calculation of binding free energies of inhibitors to plasmepsin II

Authors

  • Denise Steiner,

    1. Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland
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  • Chris Oostenbrink,

    1. Department of Material Sciences and Process Engineering, Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria
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  • François Diederich,

    1. Department of Chemistry and Applied Biosciences, Laboratory of Organic Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland
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  • Martina Zürcher,

    1. Department of Chemistry and Applied Biosciences, Laboratory of Organic Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland
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  • Wilfred F. van Gunsteren

    Corresponding author
    1. Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland
    • Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, CH-8093 Zürich, Switzerland
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Abstract

An understanding at the atomic level of the driving forces of inhibitor binding to the protein plasmepsin (PM) II would be of interest to the development of drugs against malaria. To this end, three state of the art computational techniques to compute relative free energies—thermodynamic integration (TI), Hamiltonian replica-exchange (H-RE) TI, and comparison of bound versus unbound ligand energy and entropy—were applied to a protein-ligand system of PM II and several exo-3-amino-7-azabicyclo[2.2.1]heptanes and the resulting relative free energies were compared with values derived from experimental IC50 values. For this large and flexible protein-ligand system, the simulations could not properly sample the relevant parts of the conformational space of the bound ligand, resulting in failure to reproduce the experimental data. Yet, the use of Hamiltonian replica exchange in conjunction with thermodynamic integration resulted in enhanced convergence and computational efficiency compared to standard thermodynamic integration calculations. The more approximate method of calculating only energetic and entropic contributions of the ligand in its bound and unbound states from conventional molecular dynamics (MD) simulations reproduced the major trends in the experimental binding free energies, which could be rationalized in terms of energetic and entropic characteristics of the different structural and physico-chemical properties of the protein and ligands. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011

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