Chinese Science Bulletin

, Volume 52, Issue 22, pp 3074–3088 | Cite as

Molecular motions and conformational transition between different conformational states of HIV-1 gp120 envelope glycoprotein

Articles Biophysics


The HIV-1 gp120 exterior envelope glycoprotein undergoes a series of conformational rearrangements while sequentially interacting with the receptor CD4 and coreceptor CCR5 or CXCR4 on the surface of host cells to initiate virus entry. Both the crystal structures of the HIV-1 gp120 core bound by the CD4 and antigen 17b and the SIV gp120 core pre-bound by CD4 are known. Despite the wealth of knowledge on these static snapshots of molecular conformations, the details of molecular motions involved in conformational transition that are crucial to intervention remain elusive. We presented comprehensive comparative analyses of the dynamics behaviors of the gp120 in its CD4-complexed, CD4-free and CD4-unliganded states based on the homology models with modeled V3 and V4 loops by means of CONCOORD computer simulation to generate ensembles of feasible protein structures that were subsequently analysed by essential dynamics analyses to identify preferred concerted motions. The revealed collective fluctuations are dominated by complex modes of combinational motions of the rotation/twisting, flexing/closure, and shortness/elongation between or within the inner, outer, and bridging-sheet domains, and these modes are related to the CD4 association and HIV neutralization avoidance. Further essential subspace overlap analyses were performed to quantitatively distinguish the preference for conformational transitions between the three states, revealing that the unliganded gp120 has a greater potential to translate its conformation into the conformational state adopted by the CD4-complexed gp120 than by the CD4-free gp120, whereas the CD4-free gp120 has a greater potential to translate its conformation into the unliganded state than the CD4-complexed gp120 does. These dynamics data of gp120 in its different conformations are helpful in understanding the relationship between the molecular motion/conformational transition and the function of gp120, and in gp120-structure-based subunit vaccine design.


HIV-1 gp120 comparative modeling conformational transition essential dynamics essential subspace overlap 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Barre-Sinoussi F, Chermann J C, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immunodeficiency syndrome (AIDS). Science, 1983, 220: 868–871CrossRefGoogle Scholar
  2. 2.
    Gallo R C, Salahuddin S Z, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science, 1984, 224: 500–503CrossRefGoogle Scholar
  3. 3.
    Heeney J L, Hahn B H. Vaccines and immunology: Elucidating immunity to HIV-1 and current prospects for AIDS vaccine development. AIDS, 2000, 14(Suppl): s125–s127Google Scholar
  4. 4.
    Klein E, Ho R. Challenges in the development of an effective HIV vaccine: Current approaches and future directions. Clin Ther, 2000, 22: 295–314CrossRefGoogle Scholar
  5. 5.
    Dalgleish A G, Beverley P C, Clapham P R, et al. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature, 1984, 312: 763–767CrossRefGoogle Scholar
  6. 6.
    Feng Y, Broder C C, Kennedy P E, et al. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science, 1996, 272: 872–877CrossRefGoogle Scholar
  7. 7.
    Trkola A, Dragic T, Arthos J, et al. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature, 1996, 384: 184–187CrossRefGoogle Scholar
  8. 8.
    Wu L, Gerard N P, Wyatt R, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature, 1996, 384: 179–183CrossRefGoogle Scholar
  9. 9.
    Veronese F D, de Vico A L, Copeland T D, et al. Characterization of gp41 as the transmembrane protein coded by the HTLV-III/LAV envelope gene. Science, 1985, 229: 1402–1405CrossRefGoogle Scholar
  10. 10.
    Trkola A, Purtscher M, Muster T, et al. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J Virol, 1996, 70: 1100–1108Google Scholar
  11. 11.
    Kwong P D, Wyatt R, Robinson J, et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 1998, 393: 648–659CrossRefGoogle Scholar
  12. 12.
    Kwong P D, Wyatt R, Majeed S, et al. Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates. Struct Fold Des, 2000, 8: 1329–1339CrossRefGoogle Scholar
  13. 13.
    Wyatt R, Kwong P D, Desjardins E, et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature, 1998, 393: 705–711CrossRefGoogle Scholar
  14. 14.
    Chen B, Vogan E M, Gong H, et al. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature, 2005, 433: 834–841CrossRefGoogle Scholar
  15. 15.
    Kwong P D, Doyle M L, Casper D J, et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature, 2002, 420: 678–682CrossRefGoogle Scholar
  16. 16.
    Myszka D G, Sweet R W, Hensley P, et al. Energetics of the HIV gp120-CD4 binding reaction. Proc Natl Acad Sci USA, 2000, 97: 9026–9031CrossRefGoogle Scholar
  17. 17.
    Berendsen H J C, Hayward S. Collective protein dynamics in relation to function. Curr Opin Struct Biol, 2000, 10: 165–169CrossRefGoogle Scholar
  18. 18.
    Hsu S T, Bonvin A M. Atomic insight into the CD4 binding-induced conformational changes in HIV-1 gp120. Proteins, 2004, 55: 582–593CrossRefGoogle Scholar
  19. 19.
    Pan Y, Ma B, Nussinov R. CD4 binding partially locks the bridging sheet in gp120 but leaves the beta2/3 strands flexible. J Mol Biol, 2005, 350: 514–527CrossRefGoogle Scholar
  20. 20.
    Pan Y, Ma B, Keskin O, et al. Characterization of the conformational state and flexibility of HIV-1 glycoprotein gp120 core domain. J Biol Chem, 2004, 279: 30523–30530CrossRefGoogle Scholar
  21. 21.
    de Groot B L, van Aalten D M F, Scheek R M, et al. Prediction of protein conformational freedom from distance constraints. Proteins, 1997, 29: 240–251CrossRefGoogle Scholar
  22. 22.
    Barrett C P, Noble M E. Molecular motions of human cyclin-dependent kinase 2. J Biol Chem, 2005, 280: 13993–14005CrossRefGoogle Scholar
  23. 23.
    Barrett C P, Hall B A, Noble M E. Dynamite: A simple way to gain insight into protein motions. Acta Crystallogr D Biol Crystallogr, 2004, 60: 2280–2287CrossRefGoogle Scholar
  24. 24.
    Mello L V, de Groot B L, Li S, et al. Structure and flexibility of Streptococcus agalactiae hyaluronate lyase complex with its substrate. Insights into the mechanism of processive degradation of hyaluronan. J Biol Chem, 2002, 277: 36678–36688CrossRefGoogle Scholar
  25. 25.
    Vreede J, van der Horst M A, Hellingwerf K J, et al. PAS domains. Common structure and common flexibility. J Biol Chem, 2003, 278: 18434–18439CrossRefGoogle Scholar
  26. 26.
    Liu S Q, Liu C Q, Fu Y X, Molecular motions in HIV-1 gp120 mutants reveal their preferences for different conformations. J Mol Graphics Modell, 2007, 26: 306–318CrossRefGoogle Scholar
  27. 27.
    Bairoch A, Apweiler R, Wu C H, et al. The Universal Protein Resource (UniProt). Nucl Acids Res, 2005, 33: 154–159CrossRefGoogle Scholar
  28. 28.
    Deshpande N, Addess K J, Bluhm W F, et al. Describes the capabilities of the PDB Beta site. Nucl Acids Res, 2005, 33: 233–237CrossRefGoogle Scholar
  29. 29.
    Vranken W F, Budesinsky M, Fant F, et al. The complete consensus V3 loop peptide of the envelope protein Gp120 of HIV-1 shows pronounced helical character in solution. FEBS Lett, 1995, 374: 117–121CrossRefGoogle Scholar
  30. 30.
    Sali A, Blundell T L. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol, 1993, 234: 779–815CrossRefGoogle Scholar
  31. 31.
    Amadei A, Linssen A B M, Berendsen H J C. Essential dynamics of proteins. Proteins, 1993, 17: 412–425CrossRefGoogle Scholar
  32. 32.
    Levy R, Srinivasan A, Olson W, et al. Quasiharmonic method for studying very low frequency modes in proteins. Biopolymers, 1984, 23: 1099–1112CrossRefGoogle Scholar
  33. 33.
    Garcia A E. Large-amplitude nonlinear motions in proteins. Phys Rev Lett, 1992, 68: 2696–2699CrossRefGoogle Scholar
  34. 34.
    Hayward S, Go N. Collective variable description of native protein dynamics. Annu Rev Phys Chem, 1995, 46: 223–250CrossRefGoogle Scholar
  35. 35.
    Berendsen H J C, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comp Phys Comm, 1995, 91: 43–56CrossRefGoogle Scholar
  36. 36.
    Lindahl E, Hess B, van der Spoel D. GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Mod, 2001, 7: 306–317Google Scholar
  37. 37.
    van Aalten D M F, Findlay J B C, Amadei A, et al. Essential dynamics of the cellular retinol binding protein: evidence for ligand induced conformational changes. Prot Eng, 1995, 8: 1129–1136CrossRefGoogle Scholar
  38. 38.
    van Aalten D M F, de Groot B L, Berendsen H J C, et al. A comparison of techniques for calculating protein essential dynamics. J Comp Chem, 1997, 18: 169–181CrossRefGoogle Scholar
  39. 39.
    Humphrey W, Dalke A, Schulten K. VMD—Visual molecular dynamics. J Mol Graph, 1996, 14: 33–38; 27–28CrossRefGoogle Scholar
  40. 40.
    de Groot B L, Hayward S, van Aalten D M, et al. Domain motions in bacteriophage T4 lysozyme: A comparison between molecular dynamics and crystallographic data. Proteins, 1998, 31: 116–127CrossRefGoogle Scholar
  41. 41.
    Merlino A, Vitagliano L, Ceruso M A, et al. Dynamic properties of the N-terminal swapped dimer of ribonuclease A. Biophys J, 2004, 86: 2383–2391CrossRefGoogle Scholar
  42. 42.
    Roccatano D, Daidone I, Ceruso M A, et al. Selective excitation of native fluctuations during thermal unfolding simulations: Horse Heart Cytochrome C as a case study. Biophys J, 2003, 84: 1876–1883Google Scholar
  43. 43.
    Hess B. Similarities between principal components of protein dynamics and random diffusion. Phys Rev E, 2000, 62: 8438–8448CrossRefGoogle Scholar
  44. 44.
    Laskowski R A, MacArthur M, Moss D S, et al. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr, 1993, 26: 283–291CrossRefGoogle Scholar
  45. 45.
    Baker D, Sali A. Protein structure prediction and structural genomics. Science, 2001, 294: 93–96CrossRefGoogle Scholar
  46. 46.
    Liu S Q, Liu S X, Fu Y X. Dynamic domains and geometrical properties of HIV-1 gp120 during conformational changes induced by CD4 binding. J Mol Mod, 2007, 13: 411–424CrossRefGoogle Scholar
  47. 47.
    Kolchinsky P, Mirzabekov T, Farzan M, et al. Adaptation of a CCR5-using, primary human immunodeficiency virus type 1 isolate for CD4-independent replication. J Virol, 1999, 73: 8120–8126Google Scholar

Copyright information

© Science in China Press 2007

Authors and Affiliations

  1. 1.Laboratory for Conservation and Utilization of Bio-resourcesYunnan UniversityKunmingChina
  2. 2.Human Genetics Centerthe University of Texas Health Science CenterHoustonUSA
  3. 3.Modern Biology CenterYunnan UniversityKunmingChina

Personalised recommendations