title: Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors.
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.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Kitiyaporn
authors.initials: K
authors.lastname: Wittayanarakul
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
authors.forename: Michael
authors.initials: M
authors.lastname: Feig
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011237:Predictive Value of Tests; D011522:Protons; D011789:Quantum Theory; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D011522:Protons; D014867:Water; D016333:HIV Protease