Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Probing the Conformational Control Mechanism of HIV-1 gp120: A Molecular Simulation Study
Acquired immune deficiency syndrome (AIDS), which has resulted in a catastrophic consequence to human society, is a disease of human immune system caused by infection with human immunodeficiency virus (HIV). During the infection process, the HIV-1 gp120 glycoprotein undergoes a series of conformational changes while sequentially interacting with its receptor (CD4) and co-receptor (CCR5 or CXCR4) located on the host cell surface, and therefore the dynamics of gp120 are critical for viral infection and immune evasion (Colman & Lawrence, 2003). The crystal structures of the HIV-1 gp120 core in the CD4-liganded and that of the simian immunodeficiency virus (SIV) in the CD4-unliganded states exhibit a very large conformational difference (Cα RMSD is ≈10 Å), suggesting that gp120 undergoes a drastic conformational change upon CD4 binding. However, the recently solved HIV-1 gp120 crystal structures in the absence of CD4 exhibit a CD4-liganded state, thus challenging the traditional viewpoint that achieving the CD4-liganded state requires a ligand induction (Kwon et al., 2012). In order to explain the above conflicting results, and further, to probe the control mechanism responsible for conformational equilibrium and interconversion between the liganded and unliganded states of gp120, the near-full-length gp120 structural models (comprising the N-, C-termini and loops V3 and V4 that are absent in the crystal structures) in these two states were built and were further subject to molecular dynamics (MD) and metadynamics simulations. Principal component analysis of MD trajectories reveals that the differences in motion direction between certain structural components (i.e., V1/V2 stem and V3 loop) of these two forms of gp120 tend to disrupt or re-form the bridging sheet minidomain, and therefore the largest scale motions may be related to the conformational interconversion between these two states. The free energy landscapes (FEL) constructed from the metadynamics simulations exhibit that the unliganded gp120-solvent system has a more rugged and complex free energy surface than that of the liganded gp120-solvent system, implying that gp120 has more conformational substates, a richer conformational diversity, and more complex dynamic behaviors in the unliganded state than in the liganded state. The FELs also reveal that the liganded gp120-solvent system has a lower minimum free energy level than that of the unliganded gp120-solvent system (~6.0 kJ/mol), suggesting that gp120 can transform spontaneously from the unliganded state to the liganded state in the solvent environment. As a result, it is reasonable to conclude that the liganded state represents a high-probability ground state of gp120, which has a relatively larger population and therefore is ready to be trapped under the crystallization condition. On the contrary, the relatively higher minimum free energy level of the true unliganded state has a small population, and therefore this state is difficult to be trapped in the crystallization condition. Our simulation results explain why the CD4-liganded state rather than the true unliganded conformation has been solved in the crystallographic study, and facilitate an understanding of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.
This work is supported by NSFC (Grant Nos. 31370715 and 31160181) and the National Basic Research Program of China (2013CB127500)
Kwon, Y. D., Finzi, A., Wu, X., Dogo-Isonagie, C. & Lee, L. K. et al. (2012). Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc. Natl. Acad. Sci. U S A 109, 5663-5668.
Laboratory for Conservation and Utilization of Bio-Resources