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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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Related in: MedlinePlus

Constructed FELs and free energy profiles for the unbound and bound gp120 models.(A) and (B) are FELs for the unbound and bound gp120 as a function of projections of the MD trajectory onto the first (PC1) and second (PC2) eigenvectors, respectively. The color bar represents the free energy value in unit of kJ/mol. (C) and (D) are 1D free energy profiles of these two forms of gp120 (unbound: black line; bound: red line) as a function of PC1 and PC2, respectively.
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pone-0104714-g007: Constructed FELs and free energy profiles for the unbound and bound gp120 models.(A) and (B) are FELs for the unbound and bound gp120 as a function of projections of the MD trajectory onto the first (PC1) and second (PC2) eigenvectors, respectively. The color bar represents the free energy value in unit of kJ/mol. (C) and (D) are 1D free energy profiles of these two forms of gp120 (unbound: black line; bound: red line) as a function of PC1 and PC2, respectively.

Mentions: The FELs were constructed by performing metadynamics simulations with projections of the first (PC1) and second (PC2) eigenvectors as the CV1 and CV2, respectively. These two eigenvectors span an essential subspace that contributes ∼50% to the total MSF of the conformation space sampled by the standard MD simulations. Figures 7A and B show the constructed FELs for the unbound and bound gp120, respectively, both of which present a funnel-like shape. For the unbound gp120, there are two main free energy wells/basins in the global free energy minimum region (which is arbitrarily defined as that with free energy <−163.0 kJ/mol) of the landscape, suggesting two main conformational substates, namely A and B residing within these two wells, respectively. The free energy well A is slightly larger and deeper than the well B, indicating that the substate A has a relatively larger population and lower free energy than the substate B. In the case of the bound gp120, there is only one free energy well in the global free energy minimum region, indicating only one stable conformational state residing within this well. A comparison between the full views of the FELs for these two forms of gp120 reveals that the FEL of the unbound gp120 spans larger ranges of PC1 and PC2 and exhibits a more rugged free energy surface than that of the bound gp120. For instance, the FEL of the unbound gp120 spans ranges of ∼11.6 and ∼16.0 nm along the PC1 and PC2, respectively, while the corresponding ranges for the bound gp120 are ∼7.1 and ∼7.6 nm, respectively. These results indicate that the unbound gp120 sampled a larger free energy surface than the bound gp120 during simulations. Furthermore, the unbound gp120 FEL contains more number of local free energy minima either in the global free energy minimum region (i.e., the funnel bottom) or in the region outside the global free minimum (i.e., the funnel wall), resulting in a more rugged and complex FEL of the unbound gp120 compared to that of the bound gp120.


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)

Constructed FELs and free energy profiles for the unbound and bound gp120 models.(A) and (B) are FELs for the unbound and bound gp120 as a function of projections of the MD trajectory onto the first (PC1) and second (PC2) eigenvectors, respectively. The color bar represents the free energy value in unit of kJ/mol. (C) and (D) are 1D free energy profiles of these two forms of gp120 (unbound: black line; bound: red line) as a function of PC1 and PC2, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g007: Constructed FELs and free energy profiles for the unbound and bound gp120 models.(A) and (B) are FELs for the unbound and bound gp120 as a function of projections of the MD trajectory onto the first (PC1) and second (PC2) eigenvectors, respectively. The color bar represents the free energy value in unit of kJ/mol. (C) and (D) are 1D free energy profiles of these two forms of gp120 (unbound: black line; bound: red line) as a function of PC1 and PC2, respectively.
Mentions: The FELs were constructed by performing metadynamics simulations with projections of the first (PC1) and second (PC2) eigenvectors as the CV1 and CV2, respectively. These two eigenvectors span an essential subspace that contributes ∼50% to the total MSF of the conformation space sampled by the standard MD simulations. Figures 7A and B show the constructed FELs for the unbound and bound gp120, respectively, both of which present a funnel-like shape. For the unbound gp120, there are two main free energy wells/basins in the global free energy minimum region (which is arbitrarily defined as that with free energy <−163.0 kJ/mol) of the landscape, suggesting two main conformational substates, namely A and B residing within these two wells, respectively. The free energy well A is slightly larger and deeper than the well B, indicating that the substate A has a relatively larger population and lower free energy than the substate B. In the case of the bound gp120, there is only one free energy well in the global free energy minimum region, indicating only one stable conformational state residing within this well. A comparison between the full views of the FELs for these two forms of gp120 reveals that the FEL of the unbound gp120 spans larger ranges of PC1 and PC2 and exhibits a more rugged free energy surface than that of the bound gp120. For instance, the FEL of the unbound gp120 spans ranges of ∼11.6 and ∼16.0 nm along the PC1 and PC2, respectively, while the corresponding ranges for the bound gp120 are ∼7.1 and ∼7.6 nm, respectively. These results indicate that the unbound gp120 sampled a larger free energy surface than the bound gp120 during simulations. Furthermore, the unbound gp120 FEL contains more number of local free energy minima either in the global free energy minimum region (i.e., the funnel bottom) or in the region outside the global free minimum (i.e., the funnel wall), resulting in a more rugged and complex FEL of the unbound gp120 compared to that of the bound gp120.

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
Related in: MedlinePlus