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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.

Show MeSH
Multiple sequence alignments between gp120 target sequence and sequences of the selected structural templates.(A) and (B) are alignments for constructing gp120 structural models in the CD4-bound and CD4-unbound states, respectively. HIV-1 represents the target sequence coming from HIV-1 JR-FL isolate gp160 precursor with Swiss-Prot accession number Q75760. 3JWD, 2B4C, and 3FUS represent sequences of crystal structures with PDB entries 3JWD (chain A), 2B4C (chain G), and 3FUS (chain A), respectively. It should be noted that in (B) only the segments of the N-, C-termini from 3JWD (chain A) and of the loop V3 from 2B4C (chain G) were used as templates for building corresponding structural parts of gp120. Strongly and weakly conserved residues were shaded in dark and light blue, respectively. The secondary structural elements were assigned according to the templates with red spirals and blue arrows representing α helices and β strands, respectively. The green arrows represent β strands (i.e., β5–β6 and β21–β22 in (A), and β1–β2 and β11–β12 in (B)) that can participate in the formation of the bridging sheet. The “GAG” sequence in the V1/V2 loop of gp120 is the consequence of truncation.
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pone-0104714-g001: Multiple sequence alignments between gp120 target sequence and sequences of the selected structural templates.(A) and (B) are alignments for constructing gp120 structural models in the CD4-bound and CD4-unbound states, respectively. HIV-1 represents the target sequence coming from HIV-1 JR-FL isolate gp160 precursor with Swiss-Prot accession number Q75760. 3JWD, 2B4C, and 3FUS represent sequences of crystal structures with PDB entries 3JWD (chain A), 2B4C (chain G), and 3FUS (chain A), respectively. It should be noted that in (B) only the segments of the N-, C-termini from 3JWD (chain A) and of the loop V3 from 2B4C (chain G) were used as templates for building corresponding structural parts of gp120. Strongly and weakly conserved residues were shaded in dark and light blue, respectively. The secondary structural elements were assigned according to the templates with red spirals and blue arrows representing α helices and β strands, respectively. The green arrows represent β strands (i.e., β5–β6 and β21–β22 in (A), and β1–β2 and β11–β12 in (B)) that can participate in the formation of the bridging sheet. The “GAG” sequence in the V1/V2 loop of gp120 is the consequence of truncation.

Mentions: The MODELLER software package [41] was used to build the gp120 structural models. In order to obtain an as complete as possible model in the bound state, we aligned simultaneously the target sequence to the chain G of 2B4C and chain A of 3JWD after a structural alignment between these two templates (Figure 1A). Analogously, structural alignment between 3FUS, the structural segments for the V3 loop from 2B4C and for the N- and C-termini from 3JWD was performed. This was followed by aligning the target sequence to these templates (Figure 1B) in order to obtain an as complete as possible structural model in the unbound state. 20 structural models were generated for the bound and unbound gp120, respectively, and the molecular dynamics simulated annealing (SA-MD) was performed to refine these models. The structural assessment was performed using PROCHECK [42]. The models having the minimum value of molecular probability density function were selected for following MD simulations.


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)

Multiple sequence alignments between gp120 target sequence and sequences of the selected structural templates.(A) and (B) are alignments for constructing gp120 structural models in the CD4-bound and CD4-unbound states, respectively. HIV-1 represents the target sequence coming from HIV-1 JR-FL isolate gp160 precursor with Swiss-Prot accession number Q75760. 3JWD, 2B4C, and 3FUS represent sequences of crystal structures with PDB entries 3JWD (chain A), 2B4C (chain G), and 3FUS (chain A), respectively. It should be noted that in (B) only the segments of the N-, C-termini from 3JWD (chain A) and of the loop V3 from 2B4C (chain G) were used as templates for building corresponding structural parts of gp120. Strongly and weakly conserved residues were shaded in dark and light blue, respectively. The secondary structural elements were assigned according to the templates with red spirals and blue arrows representing α helices and β strands, respectively. The green arrows represent β strands (i.e., β5–β6 and β21–β22 in (A), and β1–β2 and β11–β12 in (B)) that can participate in the formation of the bridging sheet. The “GAG” sequence in the V1/V2 loop of gp120 is the consequence of truncation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104714-g001: Multiple sequence alignments between gp120 target sequence and sequences of the selected structural templates.(A) and (B) are alignments for constructing gp120 structural models in the CD4-bound and CD4-unbound states, respectively. HIV-1 represents the target sequence coming from HIV-1 JR-FL isolate gp160 precursor with Swiss-Prot accession number Q75760. 3JWD, 2B4C, and 3FUS represent sequences of crystal structures with PDB entries 3JWD (chain A), 2B4C (chain G), and 3FUS (chain A), respectively. It should be noted that in (B) only the segments of the N-, C-termini from 3JWD (chain A) and of the loop V3 from 2B4C (chain G) were used as templates for building corresponding structural parts of gp120. Strongly and weakly conserved residues were shaded in dark and light blue, respectively. The secondary structural elements were assigned according to the templates with red spirals and blue arrows representing α helices and β strands, respectively. The green arrows represent β strands (i.e., β5–β6 and β21–β22 in (A), and β1–β2 and β11–β12 in (B)) that can participate in the formation of the bridging sheet. The “GAG” sequence in the V1/V2 loop of gp120 is the consequence of truncation.
Mentions: The MODELLER software package [41] was used to build the gp120 structural models. In order to obtain an as complete as possible model in the bound state, we aligned simultaneously the target sequence to the chain G of 2B4C and chain A of 3JWD after a structural alignment between these two templates (Figure 1A). Analogously, structural alignment between 3FUS, the structural segments for the V3 loop from 2B4C and for the N- and C-termini from 3JWD was performed. This was followed by aligning the target sequence to these templates (Figure 1B) in order to obtain an as complete as possible structural model in the unbound state. 20 structural models were generated for the bound and unbound gp120, respectively, and the molecular dynamics simulated annealing (SA-MD) was performed to refine these models. The structural assessment was performed using PROCHECK [42]. The models having the minimum value of molecular probability density function were selected for following MD simulations.

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