title: Protein conformational dynamics in the mechanism of HIV-1 protease catalysis.
abstract: We have used chemical protein synthesis and advanced physical methods to probe dynamics-function correlations for the HIV-1 protease, an enzyme that has received considerable attention as a target for the treatment of AIDS. Chemical synthesis was used to prepare a series of unique analogues of the HIV-1 protease in which the flexibility of the "flap" structures (residues 37-61 in each monomer of the homodimeric protein molecule) was systematically varied. These analogue enzymes were further studied by X-ray crystallography, NMR relaxation, and pulse-EPR methods, in conjunction with molecular dynamics simulations. We show that conformational isomerization in the flaps is correlated with structural reorganization of residues in the active site, and that it is preorganization of the active site that is a rate-limiting factor in catalysis.
authors.affiliation: Department of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Vladimir Yu
authors.initials: VY
authors.lastname: Torbeev
authors.forename: H
authors.initials: H
authors.lastname: Raghuraman
authors.forename: Donald
authors.initials: D
authors.lastname: Hamelberg
authors.forename: Marco
authors.initials: M
authors.lastname: Tonelli
authors.forename: William M
authors.initials: WM
authors.lastname: Westler
authors.forename: Eduardo
authors.initials: E
authors.lastname: Perozo
authors.forename: Stephen B H
authors.initials: SB
authors.lastname: Kent
mesh_terms: D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D016333:HIV Protease / Q000138:chemical synthesis* / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1