Prediction of HIV-1 protease/inhibitor affinity using RosettaLigand.
Predicting HIV-1 protease/inhibitor binding affinity as the difference between the free energy of the inhibitor bound and unbound state remains difficult as the unbound state exists as an ensemble of conformations with various degrees of flap opening. We improve computational prediction of protease/inhibitor affinity by invoking the hypothesis that the free energy of the unbound state while difficult to predict is less sensitive to mutation. Thereby the HIV-1 protease/inhibitor binding affinity can be approximated with the free energy of the bound state alone. Bound state free energy can be predicted from comparative models of HIV-1 protease mutant/inhibitor complexes. Absolute binding energies are predicted with R = 0.71 and SE = 5.91 kJ/mol. Changes in binding free energy upon mutation can be predicted with R = 0.85 and SE = 4.49 kJ/mol. Resistance mutations that lower inhibitor binding affinity can thereby be recognized early in HIV-1 protease inhibitor development.
Department of Chemistry, Center for Structural Biology, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
Gordon
G
Lemmon
Kristian
K
Kaufmann
Jens
J
Meiler
D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008024:Ligands; D009154:Mutation; D011485:Protein Binding; D013816:Thermodynamics
D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1