title: Quantized water access to the HIV-1 protease active site as a proposed mechanism for cooperative mutations in drug affinity.
abstract: The development of resistance to different drugs remains a major problem for a wide range of infections. In particular, combinations of specific mutations, which individually demonstrate no effect, exhibit significant cooperativity. Here we show that changes to the energy of ligand binding in different resistant HIV-1 proteases are correlated with the creation of water binding sites in the active site. This correlation is conserved across two drugs (ritonavir and lopinavir). We propose that individual mutations induce changes in flap packing that are insufficient to allow water binding but in combination allow access, leading to the observed cooperative resistance.
authors.affiliation: Centre for Computational Science, Department of Chemistry, UCL, London, UK.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hall
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.forename: Shantenu
authors.initials: S
authors.lastname: Jha
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney
mesh_terms: D020134:Catalytic Domain / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D061466:Lopinavir / Q000494:pharmacology*; D009154:Mutation; D019438:Ritonavir / Q000494:pharmacology*; D013816:Thermodynamics; D014867:Water / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D014867:Water; D061466:Lopinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir