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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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Structures and molecular surfaces of gp120 homology models.(A) and (B) are ribbon representations of the unbound and bound gp120 models, respectively. α helices are in red, β strands in blue (except for those that are able to participate in the formation of the bridging sheet), loops V3 and V4 in yellow, and bridging sheet (only in the bound gp120 models) in green. (A) and (B) were generated using the Pymol program [69]. (C) and (D) are solvent accessible surfaces of the unbound and bound gp120 models, respectively. Solvent accessible surfaces were colored according to the accessibility of residues to solvent, ranging from blue (most accessible) to red (least accessible). The long, narrow channel in the unbound gp120, and the large CD4 cavity and CD4 Phe 43 pocket in the bound gp120 were circumscribed by black dashes. These two plots were generated using the VMD program [55].
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pone-0104714-g002: Structures and molecular surfaces of gp120 homology models.(A) and (B) are ribbon representations of the unbound and bound gp120 models, respectively. α helices are in red, β strands in blue (except for those that are able to participate in the formation of the bridging sheet), loops V3 and V4 in yellow, and bridging sheet (only in the bound gp120 models) in green. (A) and (B) were generated using the Pymol program [69]. (C) and (D) are solvent accessible surfaces of the unbound and bound gp120 models, respectively. Solvent accessible surfaces were colored according to the accessibility of residues to solvent, ranging from blue (most accessible) to red (least accessible). The long, narrow channel in the unbound gp120, and the large CD4 cavity and CD4 Phe 43 pocket in the bound gp120 were circumscribed by black dashes. These two plots were generated using the VMD program [55].

Mentions: The ribbon representations of the gp120 structural models in the CD4-unbound and CD4-bound states were shown in Figures 2A and B, respectively. Both models consist of two major domains, the inner and outer domains. As shown in Figure 2A, the inner domain of the unbound model consists of the N-, C-termini, a two-stranded antiparallel β-hairpin (β1–β2), a two-helical bundle (α1–α2), and the helix α4 (which is located between the inner and outer domains). The main body of the outer domain of the unbound model is a stacked antiparallel β-barrel that lies alongside the inner domain. The V3 loop, which acts as a connection between the β6 and β7, lies beneath the distal end of the outer domain. The V4 loop protrudes from the right side of the outer domain and adopts an open conformation. In the case of the bound gp120 (Figure 2B), its inner domain comprises a six-stranded β-sandwich at the termini-proximal end in addition to the two-helical bundle (α1–α2) and α6 (corresponding to the α4 in the unbound model). Apparently, its outer domain possesses more and longer SSEs than that of the unbound gp120, although both outer domains share a common structural organization. Like what has been observed in the unbound gp120 model, the modeled loops V3 and V4 in the bound model also protrude away from the surface of the outer domain and display random-coiled conformation. It is important to note that, in the bound model, the hairpin β5–β6 (also called V1/V2 stem) from the inner domain and the hairpin β21–β22 from the outer domain constitute an antiparallel four-stranded bridging sheet minidomain that stands below the distal ends of both domains. However, such a minidomain is not found in the unbound form because of a long separation distance (∼23 Å) between the corresponding hairpins β1–β2 and β11–β12. In the bound form, the hairpin β21–β22, V1/V2 stem, loops LD, LE and V5, and α4-β17 and β23-α5 constitute an unusually large CD4-binding cavity, at whose bottom the CD4 Phe43 binding pocket lies (Figure 2D). The unbound form has no such a cavity, but instead contains a long, narrow channel that is composed of the α2, α4, β11–β12, and CD4-binding loop (CD4-BL) at the intersection surfaces of the inner and outer domains (Figure 2C).


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)

Structures and molecular surfaces of gp120 homology models.(A) and (B) are ribbon representations of the unbound and bound gp120 models, respectively. α helices are in red, β strands in blue (except for those that are able to participate in the formation of the bridging sheet), loops V3 and V4 in yellow, and bridging sheet (only in the bound gp120 models) in green. (A) and (B) were generated using the Pymol program [69]. (C) and (D) are solvent accessible surfaces of the unbound and bound gp120 models, respectively. Solvent accessible surfaces were colored according to the accessibility of residues to solvent, ranging from blue (most accessible) to red (least accessible). The long, narrow channel in the unbound gp120, and the large CD4 cavity and CD4 Phe 43 pocket in the bound gp120 were circumscribed by black dashes. These two plots were generated using the VMD program [55].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g002: Structures and molecular surfaces of gp120 homology models.(A) and (B) are ribbon representations of the unbound and bound gp120 models, respectively. α helices are in red, β strands in blue (except for those that are able to participate in the formation of the bridging sheet), loops V3 and V4 in yellow, and bridging sheet (only in the bound gp120 models) in green. (A) and (B) were generated using the Pymol program [69]. (C) and (D) are solvent accessible surfaces of the unbound and bound gp120 models, respectively. Solvent accessible surfaces were colored according to the accessibility of residues to solvent, ranging from blue (most accessible) to red (least accessible). The long, narrow channel in the unbound gp120, and the large CD4 cavity and CD4 Phe 43 pocket in the bound gp120 were circumscribed by black dashes. These two plots were generated using the VMD program [55].
Mentions: The ribbon representations of the gp120 structural models in the CD4-unbound and CD4-bound states were shown in Figures 2A and B, respectively. Both models consist of two major domains, the inner and outer domains. As shown in Figure 2A, the inner domain of the unbound model consists of the N-, C-termini, a two-stranded antiparallel β-hairpin (β1–β2), a two-helical bundle (α1–α2), and the helix α4 (which is located between the inner and outer domains). The main body of the outer domain of the unbound model is a stacked antiparallel β-barrel that lies alongside the inner domain. The V3 loop, which acts as a connection between the β6 and β7, lies beneath the distal end of the outer domain. The V4 loop protrudes from the right side of the outer domain and adopts an open conformation. In the case of the bound gp120 (Figure 2B), its inner domain comprises a six-stranded β-sandwich at the termini-proximal end in addition to the two-helical bundle (α1–α2) and α6 (corresponding to the α4 in the unbound model). Apparently, its outer domain possesses more and longer SSEs than that of the unbound gp120, although both outer domains share a common structural organization. Like what has been observed in the unbound gp120 model, the modeled loops V3 and V4 in the bound model also protrude away from the surface of the outer domain and display random-coiled conformation. It is important to note that, in the bound model, the hairpin β5–β6 (also called V1/V2 stem) from the inner domain and the hairpin β21–β22 from the outer domain constitute an antiparallel four-stranded bridging sheet minidomain that stands below the distal ends of both domains. However, such a minidomain is not found in the unbound form because of a long separation distance (∼23 Å) between the corresponding hairpins β1–β2 and β11–β12. In the bound form, the hairpin β21–β22, V1/V2 stem, loops LD, LE and V5, and α4-β17 and β23-α5 constitute an unusually large CD4-binding cavity, at whose bottom the CD4 Phe43 binding pocket lies (Figure 2D). The unbound form has no such a cavity, but instead contains a long, narrow channel that is composed of the α2, α4, β11–β12, and CD4-binding loop (CD4-BL) at the intersection surfaces of the inner and outer domains (Figure 2C).

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