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Insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of HIV-1 gp120.

Sang P, Yang LQ, Ji XL, Fu YX, Liu SQ - PLoS ONE (2014)

Bottom Line: The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations.The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization.Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China.

ABSTRACT
Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD) simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED) analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL) for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

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Properties of the projections of the merged trajectory onto the combined eigenvectors.(A) Projections of the merged trajectory (unbound: 0–60 ns; bound: 60–120 ns) onto the combined eigenvectors of 1–4 and 30. (B) Distributions of the corresponding eigenvector projections. Distinctly different distribution can only be found in the projection along the eigenvector 1. (C) Average values of the projections of the first 30 eigenvectors as a function of eigenvector index. (D) MSD values of the projections of the first 30 eigenvectors as a function of eigenvector index. The average and MSD values of the projection along a combined eigenvector were calculated separately for the two equal halves of the projection that correspond to the unbound and bound parts of gp120, respectively.
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pone-0104714-g006: Properties of the projections of the merged trajectory onto the combined eigenvectors.(A) Projections of the merged trajectory (unbound: 0–60 ns; bound: 60–120 ns) onto the combined eigenvectors of 1–4 and 30. (B) Distributions of the corresponding eigenvector projections. Distinctly different distribution can only be found in the projection along the eigenvector 1. (C) Average values of the projections of the first 30 eigenvectors as a function of eigenvector index. (D) MSD values of the projections of the first 30 eigenvectors as a function of eigenvector index. The average and MSD values of the projection along a combined eigenvector were calculated separately for the two equal halves of the projection that correspond to the unbound and bound parts of gp120, respectively.

Mentions: Combined ED analysis was performed to compare the ED properties between the unbound and bound gp120 models. Figure 6 shows the projections of the merged trajectories onto the combined eigenvectors as well as the properties of these projections. As shown in Figures 6A, B and C, only in the case of the first eigenvector can the projection be found to have significantly different distributions and average values, indicating distinctly different large concerted motions or equilibrium states between these two forms of gp120 along this combined eigenvector. Also worth noting is that the projection of the unbound gp120 exhibits a relatively inhomogeneous distribution (e.g., four peaks) while that of the bound gp120 exhibits a normal distribution (Figure 6B: top panel), suggesting a larger conformational heterogeneity (or more conformational substates) of the unbound gp120 along the first combined eigenvector.


Insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of HIV-1 gp120.

Sang P, Yang LQ, Ji XL, Fu YX, Liu SQ - PLoS ONE (2014)

Properties of the projections of the merged trajectory onto the combined eigenvectors.(A) Projections of the merged trajectory (unbound: 0–60 ns; bound: 60–120 ns) onto the combined eigenvectors of 1–4 and 30. (B) Distributions of the corresponding eigenvector projections. Distinctly different distribution can only be found in the projection along the eigenvector 1. (C) Average values of the projections of the first 30 eigenvectors as a function of eigenvector index. (D) MSD values of the projections of the first 30 eigenvectors as a function of eigenvector index. The average and MSD values of the projection along a combined eigenvector were calculated separately for the two equal halves of the projection that correspond to the unbound and bound parts of gp120, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126740&req=5

pone-0104714-g006: Properties of the projections of the merged trajectory onto the combined eigenvectors.(A) Projections of the merged trajectory (unbound: 0–60 ns; bound: 60–120 ns) onto the combined eigenvectors of 1–4 and 30. (B) Distributions of the corresponding eigenvector projections. Distinctly different distribution can only be found in the projection along the eigenvector 1. (C) Average values of the projections of the first 30 eigenvectors as a function of eigenvector index. (D) MSD values of the projections of the first 30 eigenvectors as a function of eigenvector index. The average and MSD values of the projection along a combined eigenvector were calculated separately for the two equal halves of the projection that correspond to the unbound and bound parts of gp120, respectively.
Mentions: Combined ED analysis was performed to compare the ED properties between the unbound and bound gp120 models. Figure 6 shows the projections of the merged trajectories onto the combined eigenvectors as well as the properties of these projections. As shown in Figures 6A, B and C, only in the case of the first eigenvector can the projection be found to have significantly different distributions and average values, indicating distinctly different large concerted motions or equilibrium states between these two forms of gp120 along this combined eigenvector. Also worth noting is that the projection of the unbound gp120 exhibits a relatively inhomogeneous distribution (e.g., four peaks) while that of the bound gp120 exhibits a normal distribution (Figure 6B: top panel), suggesting a larger conformational heterogeneity (or more conformational substates) of the unbound gp120 along the first combined eigenvector.

Bottom Line: The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations.The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization.Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China.

ABSTRACT
Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD) simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED) analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL) for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

Show MeSH