title: Resolution of discordant HIV-1 protease resistance rankings using molecular dynamics simulations.
abstract: The emergence of drug resistance is a major challenge for the effective treatment of HIV. In this article, we explore the application of atomistic molecular dynamics simulations to quantify the level of resistance of a patient-derived HIV-1 protease sequence to the inhibitor lopinavir. A comparative drug ranking methodology was developed to compare drug resistance rankings produced by the Stanford HIVdb, ANRS, and RegaDB clinical decision support systems. The methodology was used to identify a patient sequence for which the three rival online tools produced differing resistance rankings. Mutations at only three positions ( L10I , A71IV, and  L90M ) influenced the resistance level assigned to the sequence. We use ensemble molecular dynamics simulations to elucidate the origin of these discrepancies and the mechanism of resistance. By simulating not only the full patient sequences but also systems containing the constituent mutations, we gain insight into why resistance estimates vary and the interactions between the various mutations. In the same way, we also gain valuable knowledge of the mechanistic causes of resistance. In particular, we identify changes in the relative conformation of the two beta sheets that form the protease dimer interface which suggest an explanation of the relative frequency of different amino acids observed in patients at residue 71.
authors: Centre for Computational Science, Department of Chemistry, University College London, London WC1H 0AJ, UK.
authors: David W
authors: DW
authors: Wright
authors: Peter V
authors: PV
authors: Coveney
mesh_terms: D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009154:Mutation; D025341:Principal Component Analysis; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013816:Thermodynamics; D014867:Water / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D014867:Water; D061466:Lopinavir; D016333:HIV Protease