title: Solution structure of HIV-1 protease flaps probed by comparison of molecular dynamics simulation ensembles and EPR experiments.
abstract: The introduction of multidrug treatment regimens has dramatically prolonged the progression and survival of AIDS patients. However, the success of the long-term treatment has been hindered by strains of HIV that are increasingly resistant to inhibitors of targets such as HIV protease (HIV PR). Therefore, the need for a thorough understanding of the structure and dynamics of HIV PR and how these are altered in resistant mutants is crucial for the design of more effective treatments. Crystal structures of unbound HIV PR show significant heterogeneity and often have extensive crystal packing interactions. Recent site-directed spin labeling (SDSL) and double electron-electron resonance (DEER) spectroscopy studies characterized flap conformations in HIV-1 protease in an inhibited and uninhibited form and distinguished the extent of flap opening in an unbound form. However, the correlation between EPR-measured interspin distances and structural/dynamic features of the flaps has not been established. In this report, we link EPR-based data and 900 ns of MD simulation in explicit water to gain insight into the ensemble of conformations sampled by HIV PR flaps in solution, both in the presence and in the absence of an FDA-approved HIV PR inhibitor.
authors.affiliation: Department of Chemistry and Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Ding
authors.forename: Melinda
authors.initials: M
authors.lastname: Layten
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D003198:Computer Simulation; D004578:Electron Spin Resonance Spectroscopy; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D011487:Protein Conformation / Q000187:drug effects; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D012996:Solutions; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir