Effect Of CD4 Binding On Structural Dynamics Of HIV-1 Gp120

The first step for human HIV-1 to infect host cells is the recognition and interaction of the CD4 molecule located on the T cell surface by the gp120, a envelop glycoprotein located on the viron surface, which in turn leads to the exposure of coreceptor-binding site located on the V3 loop and bridging sheet of gp120. The next step is the further interaction of gp120 with coreceptor molecules (CCR5 or CXCR4) located on the host cell surface, and this leads to the membrane fusion between virus and cell and, further, the entry of virus into the cell. The spread of the virus among immune cells will ultimately destroy the body's immune system. Although many sets of atomic resolution crystal structures are available for HIV-1 gp120, the detailed dynamics involving structural fluctuations and conformational transitions between different states of gp120 remains to be elicited. The gp120 molecule has been considered to assume distinct conformational states before and after CD4 binding, or, alternatively, gp120 undergoes a large conformational change upon CD4 binding. Such a large conformational change has also been proposed to be one of the strategies for the virus to escape host immune response by shielding the conserved epitopes.To this end, a detailed understanding of the conformational changes and dynamic structural features of gp120 will aid in understanding clearly the mechanisms responsible for immune escape and infection by HIV-1,and can also provide useful clues for the design of anti-HIV agents and the development of vaccine.Previously determined crystallographic structures of gp120 are the structural cores that contain no peripheral loops such as the V1/V2 loop, V3 loop, and V4 loop. The Env trimer structure (gp1203-gp413) in complex with CD4 molecules, in which gp120 contains the N- and C-termini and the loops V1, V2, V3, V4 and V5 and is in the CD4-bound state, is not available from PDB protein structural database until August 2015. Two structural models, i.e., the structures of gp120 monomer (through removing the CD4 molecule) and gp120-CD4 complex, were obtained based on this trimeric structure, and these two models were used as starting structures'for performing molecular dynamics simulations to probe the effects of CD4 binding on dynamical properties and molecular motions of gp120.In order to assess quantitatively the change in structural properties caused by CD4 binding, we calculated the average geometrical properties of these two forms of gp120 based on the obtained equilibrium trajectories. These properties include the number of native contacts (NNC), number of hydrogen bonds (NHB), radius of gyration (Rg), solvent accessible surface area (SASA), and secondary structural content (SSC; number of amino acid residues within different secondary structural types). The results imply that the binding of CD4 could lead to a more compact structure and a more stable conformation of gp120, and that the monomeric gp120 experienced more drastic fluctuations than the complexed gp120 during molecular dynamics simulations. Analyses of conformational flexibility with Ca RMSF values reveal that the CD4 binding not only reduces flexibility of the peripheral loops to a certain extent but also enhances greatly the rigidity of the structural core, ultimately improving the rigidity of the entire gp120 structure. Apart from the above analyses, essential dynamics (ED) and combined ED were used to investigate changes in conformational sampling, ED properties, and molecular motion of gp120 upon CD4 binding, and the results reveal that i) the monomeric gp120 sampled a broader region in the two-dimensional conformational sub-space when compared to the complexed gp120, reflecting that the CD4 binding reduced the conformational diversity of gp120 and, as thus, confined the gp120 to few conformational states; ii) although both forms of gp120 demonstrated significant large-scale concerted motions along their first four eigenvectors, the monomeric gp120 had a larger amplitude of atomic fluctuations and experienced a larger conformational shift; iii) the monomeric and complexed gp120s exhibited distinctly different equilibrium fluctuations along the first combined eigenvector, suggesting drastic conformational changes in gpl20 upon the CD4 binding, for which the moving directions of several key structural regions most likely play roles in the function of gp120; iv) the motional modes of the complexed gp120 along its first four eigenvectors can result in various conformational changes of the CD4-binding cavity, loops V1/V2 and V3, bridging sheet, and the N-terminus, which have been related to orientation of CD4 in its binding cavity and to further binding to the coreceptor and conformational change of the gp41 fusion peptide.The present study reveals the structural dynamics-function relationship of HIV-1 gp120. The results provide not only the dynamics-related clues for a detailed understanding of the mechanisms by which HIV-1 infects host cells and escapes host immune response, but also the help in developments of anti-HIV therapeutic agents and vaccines.