Drug pressure selected mutations in HIV-1 protease alter flap conformations.
The flap conformations of two drug-resistant HIV-1 protease constructs were characterized by molecular dynamic (MD) simulations and distance measurements with pulsed electron paramagnetic resonance (EPR) spectroscopy. MD simulations accurately regenerate the experimentally determined distance profiles and provide structural interpretations of the EPR data. The combined analyses show that the average conformation of the flaps, the range of flap opening and closing, and the flexibility of the flaps differ markedly in HIV-1PR as multiple mutations arise in response to antiviral therapy, providing structural insights into the mechanism of inhibitor resistance.
Galiano
Luis
L
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, USA.
Ding
Fangyu
F
Veloro
Angelo M
AM
Blackburn
Mandy E
ME
Simmerling
Carlos
C
Fanucci
Gail E
GE
D020134:Catalytic Domain; D003198:Computer Simulation; D004578:Electron Spin Resonance Spectroscopy; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation
D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1