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The Patterns of Coevolution in Clade B HIV Envelope's N-Glycosylation Sites.

Garimalla S, Kieber-Emmons T, Pashov AD - PLoS ONE (2015)

Bottom Line: Indications of pressure to preserve the evolving glycan shield are seen as well as strong dependencies between the majority of the potential N-glycosylation sites and the rest of the structure.The map we propose fills the gap in previous attempts to tease out sequon evolution by providing a more general molecular context.Thus, it will help design strategies guiding HIV gp120 evolution in a rational way.

View Article: PubMed Central - PubMed

Affiliation: University of Michigan Health System, Ann Arbor, MI, United States of America.

ABSTRACT
The co-evolution of the potential N-glycosylation sites of HIV Clade B gp120 was mapped onto the coevolution network of the protein structure using mean field direct coupling analysis (mfDCA). This was possible for 327 positions with suitable entropy and gap content. Indications of pressure to preserve the evolving glycan shield are seen as well as strong dependencies between the majority of the potential N-glycosylation sites and the rest of the structure. These findings indicate that although mainly an adaptation against antibody neutralization, the evolving glycan shield is structurally related to the core polypeptide, which, thus, is also under pressure to reflect the changes in the N-glycosylation. The map we propose fills the gap in previous attempts to tease out sequon evolution by providing a more general molecular context. Thus, it will help design strategies guiding HIV gp120 evolution in a rational way.

No MeSH data available.


Related in: MedlinePlus

Map of the sites with the highest betweenness centrality values on the 2B4C structure—a stereo view.Red—group 1, yellow—group 2, cyan—group 3 (only positions in groups 1 and 2 are labeled). These positions are found in the membrane proximal part of the inner domain, the bridging sheet and the CD4 binding site. The pseudo-bonds indicate the immediate mfDCA couplings (ego network) of the positions in the 3 groups. (The Chimera file is S4 File).
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pone.0128664.g006: Map of the sites with the highest betweenness centrality values on the 2B4C structure—a stereo view.Red—group 1, yellow—group 2, cyan—group 3 (only positions in groups 1 and 2 are labeled). These positions are found in the membrane proximal part of the inner domain, the bridging sheet and the CD4 binding site. The pseudo-bonds indicate the immediate mfDCA couplings (ego network) of the positions in the 3 groups. (The Chimera file is S4 File).

Mentions: The effect of the evolving glycan shield on the rest of the structure was studied also in the context of the potential allosteric pathways. The latter were predicted as the shortest paths in the co-evolutionary graph. Betweenness centrality (BC) measures the proportion of shortest paths that a node lies on. In this way, BC can be used to predict the frequency with which a position participates in allosteric paths. The highest BC values clustered in three groups (S1 Fig) and the corresponding sites (3, 9 and 29 sites respectively) represented a core structure highly connected to all other sites. Fig 6 (and S4 File) maps the 29 sites common with 2B4C color coded for the group. In descending order of the centrality measure associated they represent: group 1—V346, R192 and M426; group 2—D230, K178, V270, D474, L134, E429, G152, E275 and S195 and group 3—V169, F317, D62, T236, Q170, N135, T63, E268, A219, N362, E106, F277, I154, R419, V65, N99, V182, P369, E47, I194, T140, G471, Q442, G379, M373, K232, R444, E150 and T240. None of these sites lied on paths that connected less than 149 other sites and 10 (underlined) were on shortest paths connecting more than 300 sites. The sites considered connected were those at the termini of the paths only and not the intermediates. Among the positions with the top 41 BC values there were 10 SRP (bolded), a proportion not significantly different from the overall. Neither did the distribution of SRP correlate with the classification in 3 groups with top BC. Thus, being a sequon related position did not correlate with allosteric centrality. Some SRP participated in the majority of the allosteric paths, e.g.—N362 (degree = 9) sits on allosteric paths that connect all nodes in the main component of the graph (n = 323), T236 (degree = 13) and N135 (degree = 12) each connect 297 nodes, etc. Other SRP, mostly those in the V4 and V5, were only locally connected. The node degree, the number of terminal positions of the paths involved and the BC values correlated only weakly. Interestingly, 12/41 top BC positions were found in V1/V2 region. It seems to have a central role in the structural dependencies despite its disordered conformation and much more so than the other variable regions. Group 1 and 2 of the top BC positions (n = 12) were found in the CD4 binding region, some membrane proximal positions (D230, V270 and D275), V3 (F317) and the α2-helix (V346—degree = 16, connects 289 sites, focuses most paths and is the most central position according to this graph). This set generally forms an intermediate region connecting allosteric paths that span the inner and the outer domains.


The Patterns of Coevolution in Clade B HIV Envelope's N-Glycosylation Sites.

Garimalla S, Kieber-Emmons T, Pashov AD - PLoS ONE (2015)

Map of the sites with the highest betweenness centrality values on the 2B4C structure—a stereo view.Red—group 1, yellow—group 2, cyan—group 3 (only positions in groups 1 and 2 are labeled). These positions are found in the membrane proximal part of the inner domain, the bridging sheet and the CD4 binding site. The pseudo-bonds indicate the immediate mfDCA couplings (ego network) of the positions in the 3 groups. (The Chimera file is S4 File).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482261&req=5

pone.0128664.g006: Map of the sites with the highest betweenness centrality values on the 2B4C structure—a stereo view.Red—group 1, yellow—group 2, cyan—group 3 (only positions in groups 1 and 2 are labeled). These positions are found in the membrane proximal part of the inner domain, the bridging sheet and the CD4 binding site. The pseudo-bonds indicate the immediate mfDCA couplings (ego network) of the positions in the 3 groups. (The Chimera file is S4 File).
Mentions: The effect of the evolving glycan shield on the rest of the structure was studied also in the context of the potential allosteric pathways. The latter were predicted as the shortest paths in the co-evolutionary graph. Betweenness centrality (BC) measures the proportion of shortest paths that a node lies on. In this way, BC can be used to predict the frequency with which a position participates in allosteric paths. The highest BC values clustered in three groups (S1 Fig) and the corresponding sites (3, 9 and 29 sites respectively) represented a core structure highly connected to all other sites. Fig 6 (and S4 File) maps the 29 sites common with 2B4C color coded for the group. In descending order of the centrality measure associated they represent: group 1—V346, R192 and M426; group 2—D230, K178, V270, D474, L134, E429, G152, E275 and S195 and group 3—V169, F317, D62, T236, Q170, N135, T63, E268, A219, N362, E106, F277, I154, R419, V65, N99, V182, P369, E47, I194, T140, G471, Q442, G379, M373, K232, R444, E150 and T240. None of these sites lied on paths that connected less than 149 other sites and 10 (underlined) were on shortest paths connecting more than 300 sites. The sites considered connected were those at the termini of the paths only and not the intermediates. Among the positions with the top 41 BC values there were 10 SRP (bolded), a proportion not significantly different from the overall. Neither did the distribution of SRP correlate with the classification in 3 groups with top BC. Thus, being a sequon related position did not correlate with allosteric centrality. Some SRP participated in the majority of the allosteric paths, e.g.—N362 (degree = 9) sits on allosteric paths that connect all nodes in the main component of the graph (n = 323), T236 (degree = 13) and N135 (degree = 12) each connect 297 nodes, etc. Other SRP, mostly those in the V4 and V5, were only locally connected. The node degree, the number of terminal positions of the paths involved and the BC values correlated only weakly. Interestingly, 12/41 top BC positions were found in V1/V2 region. It seems to have a central role in the structural dependencies despite its disordered conformation and much more so than the other variable regions. Group 1 and 2 of the top BC positions (n = 12) were found in the CD4 binding region, some membrane proximal positions (D230, V270 and D275), V3 (F317) and the α2-helix (V346—degree = 16, connects 289 sites, focuses most paths and is the most central position according to this graph). This set generally forms an intermediate region connecting allosteric paths that span the inner and the outer domains.

Bottom Line: Indications of pressure to preserve the evolving glycan shield are seen as well as strong dependencies between the majority of the potential N-glycosylation sites and the rest of the structure.The map we propose fills the gap in previous attempts to tease out sequon evolution by providing a more general molecular context.Thus, it will help design strategies guiding HIV gp120 evolution in a rational way.

View Article: PubMed Central - PubMed

Affiliation: University of Michigan Health System, Ann Arbor, MI, United States of America.

ABSTRACT
The co-evolution of the potential N-glycosylation sites of HIV Clade B gp120 was mapped onto the coevolution network of the protein structure using mean field direct coupling analysis (mfDCA). This was possible for 327 positions with suitable entropy and gap content. Indications of pressure to preserve the evolving glycan shield are seen as well as strong dependencies between the majority of the potential N-glycosylation sites and the rest of the structure. These findings indicate that although mainly an adaptation against antibody neutralization, the evolving glycan shield is structurally related to the core polypeptide, which, thus, is also under pressure to reflect the changes in the N-glycosylation. The map we propose fills the gap in previous attempts to tease out sequon evolution by providing a more general molecular context. Thus, it will help design strategies guiding HIV gp120 evolution in a rational way.

No MeSH data available.


Related in: MedlinePlus