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

Abstract

BackgroundThe 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.ResultsAlthough 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.ConclusionsWe 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.

Tenascin-C is an innate broad-spectrum, HIV-1–neutralizing protein in breast milk

“…4D), indicating that TNC-Env binding is dominated by electrostatic interactions. The strong influence of charge on TNC binding to Env are consistent with the reported electrostatic complementarity of the gp120 V3 loop and chemokine receptors (36)(37)(38). Thus, TNC neutralizes HIV-1 via interaction with the chemokine coreceptor binding site on the HIV-1 Env.…”

AESOP: A Python Library for Investigating Electrostatics in Protein Interactions

“…This analysis may take a significant amount of time to complete if many structures are being compared or if the grid space contains a large number of vertices. Electrostatic similarity studies are useful for comparison of global electrostatic properties of families of homologous structures (26,27) or structurally homologous repeat modules in protein structures (28).…”

Modeling interaction between gp120 HIV protein and CCR5 receptor

“…The first stages of virus infection include a series of sequential steps, which comprise interaction of viral envelope glycoprotein gp120 with CD4 receptor on the host cell surface, followed by spatial reorganisation of gp120 that allows binding to chemokine co‐receptors CXCR4 or CCR5 and fusion of viral and host cell membranes . The molecular recognition of chemokine co‐receptors is predominantly mediated by the third variable region (V3) loop of gp120, which is exposed after the interaction with the CD4 molecule . A detailed study of the interaction of gp120 with CCR5 allowed to propose a two‐site binding mechanism: the stem of V3 mediates binding to the N‐terminal tail of CCR5, while the V3 crown interacts with the second extracellular loop …”