title: Studies on adaptability of binding residues and flap region of TMC-114 resistance HIV-1 protease mutants.
abstract: Drug resistant mutations have severely restricted the success of HIV therapy. These mutations frequently involve the aspartic protease encoded by the virus. Knowledge of the molecular mechanisms underlying the conformational changes of HIV-1 protease mutants may be useful in developing more effective and longer lasting treatment regimes. The flap regions of the protease are the target of a particular type of mutations occurring far from the active site, which are able to produce significant resistance against the anti-HIV drug TMC-114. We provide insight into the molecular basis of TMC-114 resistance major flap mutations (I50V and I54M) in HIV-1 protease. It reports the shape complementarity and receptor-ligand interaction analysis supported by unrestrained all-atom molecular dynamics simulations of wild and major flap mutants of HIV-1 protease that sample large conformational changes of the flaps and active site binding residues. Both resistant flap mutants showed less atomic interaction toward TMC-114 and more structural deviation compared to wild HIV-protease. It is due to increasing flexibility at TMC-114 binding cavity and deviation of binding residues in 3-D space. Distortion in binding cavity and deviation in binding residues are the result of alteration in hydrogen bonding. Flap region also exhibited similar behaviour due to changes in number of hydrogen bonds during simulations.
authors.affiliation: Bioinformatics Division, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology University, Vellore 632014, Tamil Nadu, India. riturajpurohit@gmail.com
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
authors.forename: Rao
authors.initials: R
authors.lastname: Sethumadhavan
mesh_terms: D001665:Binding Sites; D000069454:Darunavir; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; D000069454:Darunavir