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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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Eigenvalues for the unbound and bound gp120 models as a function of eigenvector.The main plot shows the eigenvalues of only the first 30 eigenvectors. The inset shows the cumulative contribution of all the 1203 eigenvectors to the total MSF. Unbound: black line; bound: red line.
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pone-0104714-g004: Eigenvalues for the unbound and bound gp120 models as a function of eigenvector.The main plot shows the eigenvalues of only the first 30 eigenvectors. The inset shows the cumulative contribution of all the 1203 eigenvectors to the total MSF. Unbound: black line; bound: red line.

Mentions: ED analyses of MD trajectories of the unbound and bound gp120 models reveal that only a few eigenvectors possess significant eigenvalues (Figure 4). Diagonalization of the covariance matrices obtained the total MSF values of 109.0 and 50.0 nm2 for the unbound and bound gp120, respectively, indicating that the unbound gp120 experienced larger fluctuation amplitude during simulations. In particular, it is apparent that each of the first 5 eigenvectors has a larger eigenvalue for the unbound than for the bound gp120 (Figure 4), reflecting larger collective atomic fluctuations of the unbound gp120 along these eigenvectors. In addition, for the unbound and bound gp120, the first 4 and 10 eigenvectors contribute 81.4% and 93.7% and, 66.8% and 86.1% to the total MSF (see Figure 4, inset), respectively. Therefore, the first 10 eigenvectors, especially the first 4 eigenvectors, can be considered to span an essential subspace within which the large-scale concerted motions take place.


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)

Eigenvalues for the unbound and bound gp120 models as a function of eigenvector.The main plot shows the eigenvalues of only the first 30 eigenvectors. The inset shows the cumulative contribution of all the 1203 eigenvectors to the total MSF. Unbound: black line; bound: red line.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g004: Eigenvalues for the unbound and bound gp120 models as a function of eigenvector.The main plot shows the eigenvalues of only the first 30 eigenvectors. The inset shows the cumulative contribution of all the 1203 eigenvectors to the total MSF. Unbound: black line; bound: red line.
Mentions: ED analyses of MD trajectories of the unbound and bound gp120 models reveal that only a few eigenvectors possess significant eigenvalues (Figure 4). Diagonalization of the covariance matrices obtained the total MSF values of 109.0 and 50.0 nm2 for the unbound and bound gp120, respectively, indicating that the unbound gp120 experienced larger fluctuation amplitude during simulations. In particular, it is apparent that each of the first 5 eigenvectors has a larger eigenvalue for the unbound than for the bound gp120 (Figure 4), reflecting larger collective atomic fluctuations of the unbound gp120 along these eigenvectors. In addition, for the unbound and bound gp120, the first 4 and 10 eigenvectors contribute 81.4% and 93.7% and, 66.8% and 86.1% to the total MSF (see Figure 4, inset), respectively. Therefore, the first 10 eigenvectors, especially the first 4 eigenvectors, can be considered to span an essential subspace within which the large-scale concerted motions take place.

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