A diverse view of protein dynamics from NMR studies of HIV-1 protease flaps.
Internal motion in proteins fulfills a multitude of roles in biological processes. NMR spectroscopy has been applied to elucidate protein dynamics at the atomic level, albeit at a low resolution, and is often complemented by molecular dynamics simulation. However, it is critical to justify the consistency between simulation results and conclusions often drawn from multiple experiments in which uncertainties arising from assumed motional models may not be explicitly evaluated. To understand the role of the flaps of HIV-1 protease dimer in substrate recognition and protease function, many molecular dynamics simulations have been performed. The simulations have resulted in various proposed models of the flap dynamics, some of which are more consistent than others with our working model previously derived from experiments. However, using the working model to discriminate among the simulation results is not straightforward because the working model was derived from a combination of NMR experiments and crystal structure data. In this study, we use the NMR chemical shifts and relaxation data of the protease "monomer" rather than structural data to narrow down the possible conformations of the flaps of the "dimer". For the first time, we show that the tips of the flaps in the unliganded protease dimer interact with each other in solution. Accordingly, we discuss the consistency of the simulations with the model derived from all experimental data.
Ishima
Rieko
R
Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. ishima@pitt.edu
Louis
John M
JM
D016333:HIV Protease / Q000737:chemistry*; D006801:Humans; D009038:Motion; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation; D012996:Solutions
D012996:Solutions; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1