structural dynamics of hiv-1 envelope gp120 outer domain with v3 loop结构动力学的hiv - 1信封外gp120和v3环域.pdfVIP

Structural Dynamics of HIV-1 Envelope Gp120 Outer Domain with V3 Loop 1 2 3 3 1 Masaru Yokoyama *, Satoshi Naganawa , Kazuhisa Yoshimura , Shuzo Matsushita , Hironori Sato * 1 Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi Murayama-shi, Tokyo, Japan, 2 Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan, 3 Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan Abstract Background: The net charge of the hypervariable V3 loop on the HIV-1 envelope gp120 outer domain plays a key role in modulating viral phenotype. However, the molecular mechanisms underlying the modulation remain poorly understood. Methodology/Principal Findings: By combining computational and experimental approaches, we examined how V3 net charge could influence the phenotype of the gp120 interaction surface. Molecular dynamics simulations of the identical gp120 outer domain, carrying a V3 loop with net charge of +3 or +7, showed that the V3 change alone could induce global changes in fluctuation and conformation of the loops involved in binding to CD4, coreceptor and antibodies. A neutralization study using the V3 recombinant HIV-1 infectious clones showed that the virus carrying the gp120 with +3 V3, but not with +7 V3, was resistant to neutralization by anti-CD4 binding site monoclonal antibodies. An information entropy study shows that otherwise variable surface of the gp120 outer domain, such as V3 and a region around the CD4 binding loop, are less heterogeneous in the gp120 subpopulation with +