title: Rapid and accurate prediction of binding free energies for saquinavir-bound HIV-1 proteases.
abstract: To explain drug resistance by computer simulations at the molecular level, we first have to assess the accuracy of theoretical predictions. Herein we report an application of the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) technique to the ranking of binding affinities of the inhibitor saquinavir with the wild type (WT) and three resistant mutants of HIV-1 protease: L90M, G48V, and G48V/L90M. For each ligand-protein complex we report 10 ns of fully unrestrained molecular dynamics (MD) simulations with explicit solvent. We investigate convergence, internal consistency, and model dependency of MM/PBSA ligand binding energies. Converged enthalpy and entropy estimates produce ligand binding affinities within 1.5 kcal/mol of experimental values, with a remarkable level of correlation to the experimentally observed ranking of resistance levels. A detailed analysis of the enthalpic/entropic balance of drug-protease interactions explains resistance in L90M in terms of a higher vibrational entropy than in the WT complex, while G48V disrupts critical hydrogen bonds at the inhibitor's binding site and produces an altered, more unfavorable balance of Coulomb and polar desolvation energies.
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, London WC1H 0AH, UK.
authors.forename: Ileana
authors.initials: I
authors.lastname: Stoica
authors.forename: S Kashif
authors.initials: SK
authors.lastname: Sadiq
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D019258:Saquinavir / Q000737:chemistry*; D012680:Sensitivity and Specificity; D013499:Surface Properties; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019258:Saquinavir