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Molecular motions of human HIV-1 gp120 envelope glycoproteins

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Abstract

The HIV-1 gp120 exterior envelope glycoprotein undergoes a series of conformational rearrangements while sequentially interacting with the receptor CD4 and the 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 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 crucial to intervention remain elusive. We presented a comprehensive comparative analysis of dynamic behavior of gp120 in its CD4-complexed, CD4-free and CD4-unliganded states based on the homology models with modeled V3 and V4 loops. CONCOORD computer simulation was utilized to generate ensembles of feasible protein structures, which were subsequently analyzed by essential dynamics technique to identify preferred concerted motions. The revealed collective fluctuations are dominated by complex motional modes such as rotation/twisting, flexing/closing, and shortness/elongation between or within the inner, outer, and bridging-sheet domains. An attempt has been made to relate these modes to receptor/coreceptor association and neutralization avoidance. Covariance web analysis revealed four subdomains that undergo concerted motion in gp120. The structural components in gp120 that move in concert with CD4 were also identified, which may be the suitable target for inhibitor design to interrupt CD4-gp120 interaction. The differences in B-factors between the three gp120 states revealed certain structural regions that could be related either to CD4 association or to subsequent dissociation of gp120 from gp41. These dynamics data provide new insights into the structure-function relationship of gp120 and may aid in structure-based anti-HIV vaccine design.

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Abbreviations

HIV:

Human immunodeficiency virus

AIDS:

Acquired immunodeficiency syndrome

Fab:

Antigen binding fragment

SIV:

Simian immunodeficiency virus

V:

Variable loop

MD:

Molecular dynamics

ED:

Essential Dynamics

PANC:

Per-atom normalized covariance

MSF:

Mean square fluctuation

RMSD:

Root mean square deviation

CD4-BL:

CD4-binding-loop

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Acknowledgements

The authors thank High Performance Computer Center of Yunnan University for computational support. This work was supported by funds from a 973 project (2003CB415102) and partially supported by grants from Yunnan Province (2006C0008M, 07Z10756, 2007C163M) and Innovation Group Project from Yunnan University.

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Authors and Affiliations

  1. Laboratory for Conservation and Utilization of Bio-resources, Yunnan University, Kunming, 650091, People’s Republic of China

    Shu-Qun Liu & Yun-Xin Fu

  2. School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People’s Republic of China

    Shi-Xi Liu

  3. Human Genetics Center, The University of Texas Helth Science Center, Houston, TX, 77030, USA

    Yun-Xin Fu

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  1. Shu-Qun Liu
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Correspondence to Yun-Xin Fu.

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Liu, SQ., Liu, SX. & Fu, YX. Molecular motions of human HIV-1 gp120 envelope glycoproteins. J Mol Model 14, 857–870 (2008). https://doi.org/10.1007/s00894-008-0327-7

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  • DOI: https://doi.org/10.1007/s00894-008-0327-7

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