title: Flap opening in HIV-1 protease simulated by 'activated' molecular dynamics.
abstract: We have used an 'activated' molecular dynamics approach to simulate flap opening in HIV-1 protease. An initial impulse for flap opening was provided by applying harmonic constraints to non-flap residues. After an initial 'melting' phase, the two beta-hairpin structures that constitute the flaps opened to a 25 A gap within 200 ps of simulation. Analysis of backbone torsion angles suggests that flap opening is related to conformational changes at Lys 45, Met 46, Gly 52 and Phe 53. In contrast, similar molecular dynamics simulations on the M46I mutant, which is associated with drug resistance, indicates that this mutation stabilizes the flaps in a closed conformation.
authors.affiliation: Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, PRI/DynCorp, National Cancer Institute - Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Collins
authors.forename: S K
authors.initials: SK
authors.lastname: Burt
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D004352:Drug Resistance, Microbial; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D016333:HIV Protease