Abstract
The entry of human immunodeficiency virus type I (HIV-1) into host cells is initiated by binding to the cell-surface receptor CD4, which induces a conformational transition of the envelope (Env) glycoprotein gp120 from the closed, unliganded state to the open, CD4-bound state. Despite many available structures in these two states, detailed aspects on the dynamics and thermodynamics of gp120 remain elusive. Here, we performed microsecond-scale (μs-scale) multiple-replica molecular dynamics (MD) simulations to explore the differences in the conformational dynamics, protein motions, and thermodynamics between the unliganded and CD4-bound/complexed forms of gp120. Comparative analyses of MD trajectories reveal that CD4 binding promotes the structural deviations/changes and conformational flexibility, loosens the structural packing, and complicates the molecular motions of gp120. Comparison of the constructed free energy landscapes (FELs) reveals that the CD4-complexed gp120 has more conformational substates, larger conformational entropy, and lower thermostability than the unliganded form. Therefore, the unliganded conformation represents a structurally and energetically stable "ground state" for the full-length gp120. The observed great increase in the mobility of V1/V2 and V3 along with their more versatile movement directions in the CD4-bound gp120 compared to the unliganded form suggests that their orientations with respect to each other and to the structural core determine the differences in the conformational dynamics and thermodynamics between the two gp120 forms. The results presented here provide a basis by which to better understand the functional and immunological properties of gp120 and, furthermore, to deploy appropriate strategies for the development of anti-HIV-1 drugs or vaccines.
Highlights
In contrast to the standard type I membrane fusion mechanism of the enveloped viruses,[7] HIV-1 has evolved a two-step mechanism to enter the target cell via sequential binding of gp[120] to two distinct receptors, the receptor CD4 and the coreceptor C–C chemokine receptor type 5 (CCR5) or C–X–C chemokine receptor type 4 (CXCR4).[8,9,10] Structural studies have revealed that before CD4 binding, Env trimer adopts a closed unliganded conformation,[11,12,13,14] in which the inter-protomer noncovalent contacts among V1/V2 and V3 of gp[120] subunits lock the trimer crown and the V1/V2 region packs against the V3 loop and buries the coreceptor-binding site
Two structural models, the near full-length monomeric gp[120] and the gp120-CD4 complex were subjected to multiple-replica molecular dynamics (MD) simulations to investigate the differences in the conformational dynamics, molecular motions, and thermodynamics between the unliganded and CD4-bound forms of gp[120]
It can be expected that the type and size of glycans would influence the fluctuations of the protein regions neighboring the N-linked glycosylation sites due to steric hindrance and weight contribution from glycans, previous MD simulation studies on gp120s with the glycosylated and non-glycosylated V3 loop showed no significant differences in the Ca-atom fluctuations between these two forms of gp[120], especially between V3 loops.[35,36]
Summary
In contrast to the standard type I membrane fusion mechanism of the enveloped viruses,[7] HIV-1 has evolved a two-step mechanism to enter the target cell via sequential binding of gp[120] to two distinct receptors, the receptor CD4 and the coreceptor C–C chemokine receptor type 5 (CCR5) or C–X–C chemokine receptor type 4 (CXCR4).[8,9,10] Structural studies have revealed that before CD4 binding, Env trimer adopts a closed unliganded conformation,[11,12,13,14] in which the inter-protomer noncovalent contacts among V1/V2 and V3 of gp[120] subunits lock the trimer crown and the V1/V2 region packs against the V3 loop and buries the coreceptor-binding site.
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