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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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Comparison between the structural flexibility of the unbound and bound gp120 models.(A) Per-residue average backbone RMSF profiles calculated from MD trajectories of the unbound (black line) and bound (red line) gp120. Note that the residues 127–191 corresponding to the V1/V2 loop are absent in our models. Loops V3, V4, V5, LC, LD and LF, and some of SSEs were marked according to the bound gp120 model. CD4-BL represents the CD4-binding loop. (B) and (C) are 3D backbone representations of the unbound and bound gp120 models that are colored according to the per-residue average backbone RMSF values, respectively. The color scale ranges from red to blue, with red corresponding to the thinnest backbone with the lowest RMSF value and blue corresponding to the thickest backbone with the highest RMSF value. (B) and (C) were generated using UCSF Chimera [70].
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pone-0104714-g003: Comparison between the structural flexibility of the unbound and bound gp120 models.(A) Per-residue average backbone RMSF profiles calculated from MD trajectories of the unbound (black line) and bound (red line) gp120. Note that the residues 127–191 corresponding to the V1/V2 loop are absent in our models. Loops V3, V4, V5, LC, LD and LF, and some of SSEs were marked according to the bound gp120 model. CD4-BL represents the CD4-binding loop. (B) and (C) are 3D backbone representations of the unbound and bound gp120 models that are colored according to the per-residue average backbone RMSF values, respectively. The color scale ranges from red to blue, with red corresponding to the thinnest backbone with the lowest RMSF value and blue corresponding to the thickest backbone with the highest RMSF value. (B) and (C) were generated using UCSF Chimera [70].

Mentions: Per-residue average backbone root mean square fluctuation (RMSF) values were computed based on the MD trajectories to evaluate and compare the structural flexibility between the unbound and bound gp120. Figure 3 shows the RMSF values as a function of residue number as well as the 3D backbone representations of gp120 colored according to the RMSF values. Figure 3A shows clearly that the bound gp120 has an overall lower flexibility (or higher rigidity) than the unbound gp120 with the exception of only a very limited number of sites such as the N-terminus and hairpin β5–β6. Also of note is that the V3 loops of both models have similar RMSF values. For both forms of gp120, the common high-flexibility regions, arbitrarily defined as those with RMSF>0.3 nm, include the loops V3, V4 and V5, and the N- and C-termini (Figure 3A). The structural cores of both forms of gp120 have lower RMSF values than the external loops and, as thus demonstrate a high rigidity, which can be more intuitively observed in Figures 3B and C. The high rigidity of the structural cores is due to their small structural deviations with respect to the starting structures during MD simulations; while the increased structural deviations or instability of the entire structures arise mainly from the high flexibility of the external loops (Table S2). We consider that it is the high flexibility of the external loops that makes it difficult to crystallize gp120 unless they are truncated.


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)

Comparison between the structural flexibility of the unbound and bound gp120 models.(A) Per-residue average backbone RMSF profiles calculated from MD trajectories of the unbound (black line) and bound (red line) gp120. Note that the residues 127–191 corresponding to the V1/V2 loop are absent in our models. Loops V3, V4, V5, LC, LD and LF, and some of SSEs were marked according to the bound gp120 model. CD4-BL represents the CD4-binding loop. (B) and (C) are 3D backbone representations of the unbound and bound gp120 models that are colored according to the per-residue average backbone RMSF values, respectively. The color scale ranges from red to blue, with red corresponding to the thinnest backbone with the lowest RMSF value and blue corresponding to the thickest backbone with the highest RMSF value. (B) and (C) were generated using UCSF Chimera [70].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g003: Comparison between the structural flexibility of the unbound and bound gp120 models.(A) Per-residue average backbone RMSF profiles calculated from MD trajectories of the unbound (black line) and bound (red line) gp120. Note that the residues 127–191 corresponding to the V1/V2 loop are absent in our models. Loops V3, V4, V5, LC, LD and LF, and some of SSEs were marked according to the bound gp120 model. CD4-BL represents the CD4-binding loop. (B) and (C) are 3D backbone representations of the unbound and bound gp120 models that are colored according to the per-residue average backbone RMSF values, respectively. The color scale ranges from red to blue, with red corresponding to the thinnest backbone with the lowest RMSF value and blue corresponding to the thickest backbone with the highest RMSF value. (B) and (C) were generated using UCSF Chimera [70].
Mentions: Per-residue average backbone root mean square fluctuation (RMSF) values were computed based on the MD trajectories to evaluate and compare the structural flexibility between the unbound and bound gp120. Figure 3 shows the RMSF values as a function of residue number as well as the 3D backbone representations of gp120 colored according to the RMSF values. Figure 3A shows clearly that the bound gp120 has an overall lower flexibility (or higher rigidity) than the unbound gp120 with the exception of only a very limited number of sites such as the N-terminus and hairpin β5–β6. Also of note is that the V3 loops of both models have similar RMSF values. For both forms of gp120, the common high-flexibility regions, arbitrarily defined as those with RMSF>0.3 nm, include the loops V3, V4 and V5, and the N- and C-termini (Figure 3A). The structural cores of both forms of gp120 have lower RMSF values than the external loops and, as thus demonstrate a high rigidity, which can be more intuitively observed in Figures 3B and C. The high rigidity of the structural cores is due to their small structural deviations with respect to the starting structures during MD simulations; while the increased structural deviations or instability of the entire structures arise mainly from the high flexibility of the external loops (Table S2). We consider that it is the high flexibility of the external loops that makes it difficult to crystallize gp120 unless they are truncated.

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