Limits...
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.

Show MeSH
Porcupine plots of the large concerted motions along the first 4 eigenvectors.(A)–(D) are motion modes along eigenvectors 1–4 of the unbound gp120, respectively. (E)–(H) are motion modes along eigenvectors 1–4 of the bound gp120, respectively. For (A), (C), (D), (G), and (H), the view is looking towards the center between the inner and outer domains. For (B), (E), and (F), the view is from the inner to outer domains. The color of the cone/porcupine ranges from blue to red, with blue corresponding to the shortest cone/porcupine with the smallest atomic displacement magnitude and red corresponding to the longest cone/porcupine with the largest atomic displacement magnitude.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126740&req=5

pone-0104714-g005: Porcupine plots of the large concerted motions along the first 4 eigenvectors.(A)–(D) are motion modes along eigenvectors 1–4 of the unbound gp120, respectively. (E)–(H) are motion modes along eigenvectors 1–4 of the bound gp120, respectively. For (A), (C), (D), (G), and (H), the view is looking towards the center between the inner and outer domains. For (B), (E), and (F), the view is from the inner to outer domains. The color of the cone/porcupine ranges from blue to red, with blue corresponding to the shortest cone/porcupine with the smallest atomic displacement magnitude and red corresponding to the longest cone/porcupine with the largest atomic displacement magnitude.

Mentions: Figure 5 shows, in porcupine representation, the large concerted motions (or motion modes) along the first 4 eigenvectors of the unbound and bound gp120 models. The most significant motion mode along eigenvector 1 of the unbound gp120 can be described as common rotations of the inner and outer domains around an axis running through the center between these two domains, resulting in a large anticlockwise vortex as shown in Figure 5A. The V3 loop from the outer domain and the N- and C-termini from the inner domain, which have the largest conformational displacements, rotate concertedly in an opposite direction relative to the large vortex. Regions with a moderate displacement magnitude include the V1/V2 stem of the inner domain and the loops V4, V5 and LE of the outer domain. The smallest displacements were observed in the major part of the structural core. The motion mode along the second eigenvector of the unbound gp120 displays as a large anticlockwise vortex that rotates around an axis connecting the centers of the inner and outer domains (Figure 5B). The largest displacements occur on the V3 loop and V1/V2 stem, which move in opposite directions with respect to each other, leading to a mutual approach between them. Other external loops have moderate displacements and rotate concertedly around the structural core, which has the smallest displacement magnitude. In the third ranked mode of the unbound gp120 (Figure 5C), the inner and outer domains rotate in opposite directions around an axis running through the center between these two domains, resulting in a twist of one domain relative to the other. The entire structure has a relatively small displacement magnitude except for the distal end of the V3 loop, which moves in an opposite direction with respect to its base, resulting in a twist of the this loop. It appears that in the fourth ranked mode, there is no apparent rotation or twist between the inner and outer domains (Figure 5D). However, the opposite motion directions between the inner and outer domains, in particular between their upper parts, seem to widen the gp120 molecule.


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)

Porcupine plots of the large concerted motions along the first 4 eigenvectors.(A)–(D) are motion modes along eigenvectors 1–4 of the unbound gp120, respectively. (E)–(H) are motion modes along eigenvectors 1–4 of the bound gp120, respectively. For (A), (C), (D), (G), and (H), the view is looking towards the center between the inner and outer domains. For (B), (E), and (F), the view is from the inner to outer domains. The color of the cone/porcupine ranges from blue to red, with blue corresponding to the shortest cone/porcupine with the smallest atomic displacement magnitude and red corresponding to the longest cone/porcupine with the largest atomic displacement magnitude.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g005: Porcupine plots of the large concerted motions along the first 4 eigenvectors.(A)–(D) are motion modes along eigenvectors 1–4 of the unbound gp120, respectively. (E)–(H) are motion modes along eigenvectors 1–4 of the bound gp120, respectively. For (A), (C), (D), (G), and (H), the view is looking towards the center between the inner and outer domains. For (B), (E), and (F), the view is from the inner to outer domains. The color of the cone/porcupine ranges from blue to red, with blue corresponding to the shortest cone/porcupine with the smallest atomic displacement magnitude and red corresponding to the longest cone/porcupine with the largest atomic displacement magnitude.
Mentions: Figure 5 shows, in porcupine representation, the large concerted motions (or motion modes) along the first 4 eigenvectors of the unbound and bound gp120 models. The most significant motion mode along eigenvector 1 of the unbound gp120 can be described as common rotations of the inner and outer domains around an axis running through the center between these two domains, resulting in a large anticlockwise vortex as shown in Figure 5A. The V3 loop from the outer domain and the N- and C-termini from the inner domain, which have the largest conformational displacements, rotate concertedly in an opposite direction relative to the large vortex. Regions with a moderate displacement magnitude include the V1/V2 stem of the inner domain and the loops V4, V5 and LE of the outer domain. The smallest displacements were observed in the major part of the structural core. The motion mode along the second eigenvector of the unbound gp120 displays as a large anticlockwise vortex that rotates around an axis connecting the centers of the inner and outer domains (Figure 5B). The largest displacements occur on the V3 loop and V1/V2 stem, which move in opposite directions with respect to each other, leading to a mutual approach between them. Other external loops have moderate displacements and rotate concertedly around the structural core, which has the smallest displacement magnitude. In the third ranked mode of the unbound gp120 (Figure 5C), the inner and outer domains rotate in opposite directions around an axis running through the center between these two domains, resulting in a twist of one domain relative to the other. The entire structure has a relatively small displacement magnitude except for the distal end of the V3 loop, which moves in an opposite direction with respect to its base, resulting in a twist of the this loop. It appears that in the fourth ranked mode, there is no apparent rotation or twist between the inner and outer domains (Figure 5D). However, the opposite motion directions between the inner and outer domains, in particular between their upper parts, seem to widen the gp120 molecule.

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