Abstract
Human immunodeficiency virus type-1 (HIV-1) infection is triggered by its envelope (Env) glycoprotein gp120 binding to the host-cell receptor CD4. Although structures of Env/gp120 in the liganded state are known, detailed information about dynamics of the liganded gp120 has remained elusive. Two structural models, the CD4-free gp120 and the gp120-CD4 complex, were subjected to µs-scale multiple-replica molecular dynamics (MD) simulations to probe the effects of CD4 binding on the conformational dynamics, molecular motions, and thermodynamics of gp120. Comparative analyses of MD trajectories in terms of structural deviation and conformational flexibility reveal that CD4 binding effectively suppresses the overall conformational fluctuations of gp120. Despite the largest fluctuation amplitude of the V1/V2 region in both forms of gp120, the presence of CD4 prevents it from approaching the gp120 core. Comparison of the constructed free energy landscapes (FELs) shows that CD4 binding reduces the conformational entropy and conformational diversity while enhancing the stability of gp120. Further comparison of the representative structures extracted from free energy basins/minima of FELs reveals that CD4 binding weakens the reorientation ability of V1/V2 and hence hinders gp120 from transitioning out of the liganded state to the unliganded state. Therefore, locking gp120 conformation via restraining V1/V2 reorientation with small molecules seems to be a promising strategy to control HIV-1 infection. Our computer simulation results support the conformational selection mechanism for CD4 binding to gp120 and facilitate the understanding of HIV-1 immune evasion mechanisms.
Highlights
The viral envelope spike (Env), which is the infection machine of HIV type I (HIV-1), is a trimeric assembly composed of three external glycoprotein gp120 subunits and three transmembrane glycoprotein gp41 subunits [1]
Aiming to probe the effects of CD4 binding on the conformational dynamics, molecular motions, and thermodynamics of gp120, we performed a series of multiple-replica molecular dynamics (MD) simulations on both systems, with the total simulation period reaching 2 μs
Our results reveal that CD4 binding suppresses the conformational fluctuations of gp120, while CD4 removal allows gp120 to transition to the unliganded state, providing a basis by which to better understand the mechanisms of receptor association and Human immunodeficiency virus type-1 (HIV-1) immune evasion
Summary
The viral envelope spike (Env), which is the infection machine of HIV type I (HIV-1), is a trimeric assembly composed of three external glycoprotein gp120 subunits and three transmembrane glycoprotein gp subunits [1]. The virally encoded glycoprotein gp120 is located on the viron’s surface and is responsible for interactions with the host receptors, but is the sole target of neutralizing antibodies. In contrast to a general membrane fusion mechanism of enveloped viruses, HIV-1 evolves a special two-step infection strategy to protect its conserved functional sites from attack by antibodies via successively binding to the receptor CD4 and the coreceptor CCR5/CXCR4 on the host cell’s surface [2,3]. Binding of CD4 by gp120 has been shown to play an intermediate role in viral infection through inducing large gp120 structural arrangements that promote the maturation of the CD4 binding site (CD4bs) and exposure of the coreceptor binding site [4]. In the newly developed clinical trial it has been shown that the combination of various anti-HIV-1 antibodies can maintain long-term viral suppression [6]
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