Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

The mutual orientation between V1/V2 and V3 is the structural determinant of HIV-1 gp120 conformational states and dynamics

The trimeric envelope spike (Env), which is the infection machinery of HIV-1 and the sole target of protective neutralizing antibodies, is composed of three external glycoprotein gp120 subunits associated non-covalently with three transmembrane glycoprotein gp41 subunits. The entry of HIV-1 is initiated by binding of gp120 to the cell-surface receptor CD4, which induces substantial changes in gp120 conformation involving the reorientation of the V1/V2 region relative to the V3 loop, rearrangements of the bridging-sheet elements, and formation and exposure of the coreceptor-binding site, ultimately leading to the transition of Env from an unliganded “closed” state to a CD4-bound “open” conformation (Guttman et al., 2014). Although structural studies have provided valuable information on various states of Env/gp120, the detailed questions on many dynamic aspects of gp120, such as what the differences in conformational dynamics and thermodynamics are between the unliganded and CD4-bound states, which structural elements determine these differences, and how gp120 regulates transition between different states, still remain answered. To answer these questions, we have performed a series of multiple-replica molecular dynamics simulations on the three structural models (i.e., the unliganded gp120, the CD4-free gp120 in the CD4-bound state, and the gp120-CD4 complex), with the cumulative simulation time length reaching 3 µs. Comparative analyses of their respective concatenated equilibrium trajectories in terms of structural deviation and conformational flexibility reveal that the CD4-free and CD4-complexed gp120s are more structurally mobile and conformationally flexible than the unliganded gp120. The most pronounced differences in the local flexibility between the unliganded and CD4-complexed/free gp120s were observed in the V1/V2 region and V3 loop, which exhibit significantly higher C root-mean-square-fluctuation values in the latters than in the former due to the dissociation between and full exposure of V1/V2 and V3. Analyses of the largest-amplitude motion modes indicate that in the CD4-free gp120, the mutual approach between V1/V2 and V3 could lead to the conformational transition to the unliganded state. Comparison of the constructed free energy landscapes (FELs) shows that CD4-complexed and CD4-free gp120s have larger conformational entropy, richer conformational diversity, and lower thermal stability than the unliganded gp120. Further comparison of the representative structures extracted from the free energy basins of FELs reveals that the presence of CD4 weakens the reorientation ability of V1/V2 relative to V3 and therefore restricts the conformational transition from the CD4-bound state to the unliganded state. Therefore, it can be concluded that the mutual orientation of the V1/V2 region with respective to the V3 loop is not only a major marker for distinguishing between the unliganded and CD4-bound states, but determines also the differences in the conformational dynamics and thermodynamics between these two states. Locking gp120 conformation via restraining mutual reorientations betweenV1/V2 and V3 with small molecules seems to be a promising strategy to control HIV-1 infection (Li, Deng, Yang, Sang, & Liu, 2019).

This research has been supported by NSFC of China (Nos. 31370715 and 31160181) and Programs for Excellent Young Talents and Donglu Scholar in the Yunnan University.


    Guttman, M., Garcia, N. K., Cupo, A., Matsui, T., Julien, J. P., Sanders, R. W., . . . Lee, K. K. (2014). CD4-Induced activation in a soluble HIV-1 Env trimer. Structure, 22, 974-984.

    Li, Y., Deng, L., Yang, L. Q., Sang, P., & Liu, S. Q. (2019). Effects of CD4 binding on conformational dynamics, molecular motions, and thermodynamics of HIV-1 gp120. International Journal of Molecular Sciences, 20, 260.

Yi Li
Lei Deng
Yan Tao
Shu-Qun Liu*

State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan & School of Life Sciences
Yunnan University
Kunming 650091, China

*Email: shuqunliu@gmail.com
Phone: (86)871-65031093