Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors

Authors

  • Kitiyaporn Wittayanarakul,

    1. Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
    Search for more papers by this author
  • Supot Hannongbua,

    1. Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
    Search for more papers by this author
  • Michael Feig

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1319
    2. Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1319
    • Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
    Search for more papers by this author

Abstract

Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV-1 protease. An MMPB/SA-type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme-inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV-1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008

Ancillary