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Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties.

López de Victoria A, Kieslich CA, Rizos AK, Krambovitis E, Morikis D - BMC Biophys (2012)

Bottom Line: We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences.This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex.We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, University of California, Riverside 92521, USA. dmorikis@engr.ucr.edu.

ABSTRACT

Background: The V3 loop of the glycoprotein gp120 of HIV-1 plays an important role in viral entry into cells by utilizing as coreceptor CCR5 or CXCR4, and is implicated in the phenotypic tropisms of HIV viruses. It has been hypothesized that the interaction between the V3 loop and CCR5 or CXCR4 is mediated by electrostatics. We have performed hierarchical clustering analysis of the spatial distributions of electrostatic potentials and charges of V3 loop structures containing consensus sequences of HIV-1 subtypes.

Results: Although the majority of consensus sequences have a net charge of +3, the spatial distribution of their electrostatic potentials and charges may be a discriminating factor for binding and infectivity. This is demonstrated by the formation of several small subclusters, within major clusters, which indicates common origin but distinct spatial details of electrostatic properties. Some of this information may be present, in a coarse manner, in clustering of sequences, but the spatial details are largely lost. We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences. We also make correlations between clustering of electrostatic potentials and net charge, coreceptor selectivity, global prevalence, and geographic distribution. Finally, we interpret coreceptor selectivity based on the N6X7T8/S8X9 sequence glycosylation motif, the specific positive charge location according to the 11/24/25 rule, and the overall charge and electrostatic potential distribution.

Conclusions: We propose that in addition to the sequence and the net charge of the V3 loop of each subtype, the spatial distributions of electrostatic potentials and charges may also be important factors for receptor recognition and binding and subsequent viral entry into cells. This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex. We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.

No MeSH data available.


Related in: MedlinePlus

Charge distribution clustering analysis of the HIV-1 subtypes, from the year 2009 consensus sequences and structural template derived from the gp120 structure with PDB Code 2QAD. The horizontal axis of the dendrogram represents charge similarity distance. The net charge, global prevalence, coreceptor selectivity and geographies of each subtype are indicated in the figure for each subtype. N/A denotes that information was not available. Green circles in the branches of the dendrogram denote intersection points between net charges or infected population. The symbol * refers to the global prevalence of Subtype B which includes the two crystal structural templates (from 2QAD and 2B4C). The symbol # refers to the global prevalence of Subtype D which includes D and D35, combined.
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Figure 4: Charge distribution clustering analysis of the HIV-1 subtypes, from the year 2009 consensus sequences and structural template derived from the gp120 structure with PDB Code 2QAD. The horizontal axis of the dendrogram represents charge similarity distance. The net charge, global prevalence, coreceptor selectivity and geographies of each subtype are indicated in the figure for each subtype. N/A denotes that information was not available. Green circles in the branches of the dendrogram denote intersection points between net charges or infected population. The symbol * refers to the global prevalence of Subtype B which includes the two crystal structural templates (from 2QAD and 2B4C). The symbol # refers to the global prevalence of Subtype D which includes D and D35, combined.

Mentions: The clustering of the distribution of charges in space for each subtype is shown in Figure 4. Some clusters within this dendrogram can be found in Figures 2 and 3 (e.g., H and CPX). However, the subtypes are mostly mixed within the +1/+2/+3 supercluster. In general, charge distribution does not depict subtle differences between the subtypes. This is because charges are localized in the structure and are independent from each other. However, electrostatic potentials, generated by these charges, have additional features. First, electrostatic potentials account for dielectric and ionic screening. Because of the latter, we observe differences in the magnitudes and shapes of electrostatic potentials in Figures 2 and 3. Second, electrostatic potentials account for spatial enhancements (additive effect of potentials with same signs) or spatial cancellations (subtractive effect of potentials with opposite signs).


Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties.

López de Victoria A, Kieslich CA, Rizos AK, Krambovitis E, Morikis D - BMC Biophys (2012)

Charge distribution clustering analysis of the HIV-1 subtypes, from the year 2009 consensus sequences and structural template derived from the gp120 structure with PDB Code 2QAD. The horizontal axis of the dendrogram represents charge similarity distance. The net charge, global prevalence, coreceptor selectivity and geographies of each subtype are indicated in the figure for each subtype. N/A denotes that information was not available. Green circles in the branches of the dendrogram denote intersection points between net charges or infected population. The symbol * refers to the global prevalence of Subtype B which includes the two crystal structural templates (from 2QAD and 2B4C). The symbol # refers to the global prevalence of Subtype D which includes D and D35, combined.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295656&req=5

Figure 4: Charge distribution clustering analysis of the HIV-1 subtypes, from the year 2009 consensus sequences and structural template derived from the gp120 structure with PDB Code 2QAD. The horizontal axis of the dendrogram represents charge similarity distance. The net charge, global prevalence, coreceptor selectivity and geographies of each subtype are indicated in the figure for each subtype. N/A denotes that information was not available. Green circles in the branches of the dendrogram denote intersection points between net charges or infected population. The symbol * refers to the global prevalence of Subtype B which includes the two crystal structural templates (from 2QAD and 2B4C). The symbol # refers to the global prevalence of Subtype D which includes D and D35, combined.
Mentions: The clustering of the distribution of charges in space for each subtype is shown in Figure 4. Some clusters within this dendrogram can be found in Figures 2 and 3 (e.g., H and CPX). However, the subtypes are mostly mixed within the +1/+2/+3 supercluster. In general, charge distribution does not depict subtle differences between the subtypes. This is because charges are localized in the structure and are independent from each other. However, electrostatic potentials, generated by these charges, have additional features. First, electrostatic potentials account for dielectric and ionic screening. Because of the latter, we observe differences in the magnitudes and shapes of electrostatic potentials in Figures 2 and 3. Second, electrostatic potentials account for spatial enhancements (additive effect of potentials with same signs) or spatial cancellations (subtractive effect of potentials with opposite signs).

Bottom Line: We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences.This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex.We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, University of California, Riverside 92521, USA. dmorikis@engr.ucr.edu.

ABSTRACT

Background: The V3 loop of the glycoprotein gp120 of HIV-1 plays an important role in viral entry into cells by utilizing as coreceptor CCR5 or CXCR4, and is implicated in the phenotypic tropisms of HIV viruses. It has been hypothesized that the interaction between the V3 loop and CCR5 or CXCR4 is mediated by electrostatics. We have performed hierarchical clustering analysis of the spatial distributions of electrostatic potentials and charges of V3 loop structures containing consensus sequences of HIV-1 subtypes.

Results: Although the majority of consensus sequences have a net charge of +3, the spatial distribution of their electrostatic potentials and charges may be a discriminating factor for binding and infectivity. This is demonstrated by the formation of several small subclusters, within major clusters, which indicates common origin but distinct spatial details of electrostatic properties. Some of this information may be present, in a coarse manner, in clustering of sequences, but the spatial details are largely lost. We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences. We also make correlations between clustering of electrostatic potentials and net charge, coreceptor selectivity, global prevalence, and geographic distribution. Finally, we interpret coreceptor selectivity based on the N6X7T8/S8X9 sequence glycosylation motif, the specific positive charge location according to the 11/24/25 rule, and the overall charge and electrostatic potential distribution.

Conclusions: We propose that in addition to the sequence and the net charge of the V3 loop of each subtype, the spatial distributions of electrostatic potentials and charges may also be important factors for receptor recognition and binding and subsequent viral entry into cells. This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex. We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.

No MeSH data available.


Related in: MedlinePlus