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Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region.

ABSTRACT: Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C). Homology modeling was used to create models of the gp120 proteins. Using monomers of the gp120 protein, we applied extensive molecular dynamics simulations to obtain dominant morphologies that represent a variety of open-closed states of the V3 loop to examine the interaction of 112 ligands of the repeating units of DCSti-alt-MA docked to the V3 loop and surrounding residues. Using the distance between the V1/V2 and V3 loops of gp120 as a metric, we revealed through MD simulations that gp120 from the lab-adapted strains (BaL and IIIb), which are more susceptible to inhibition by DCSti-alt-MA, clearly transitioned to the closed state in one replicate of each simulation set, whereas none of the replicates from the Tier II strains (92UG037 and JR-CSF) did so. Docking repeat unit microspecies to the gp120 protein before and after MD simulation enabled identification of residues that were key for binding. Notably, only a few residues were found to be important for docking both before and after MD simulation as a result of the conformational heterogeneity provided by the simulations. Consideration of the residues that were consistently involved in interactions with the ligand revealed the importance of both hydrophilic and hydrophobic moieties of the ligand for effective binding. The results also suggest that polymers of DCSti-alt-MA with repeating units of different configurations may have advantages for therapeutic efficacy.

SUBMITTER: Hollingsworth LR

PROVIDER: S-EPMC5773097 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region.

Hollingsworth Louis R LR Brown Anne M AM Gandour Richard D RD Bevan David R DR

PloS one 20180118 1

Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of t ...[more]

PMID: 29346393

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Project description: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.

Project description:HIV-1 cell entry commonly uses, in addition to CD4, one of the chemokine receptors CCR5 or CXCR4 as coreceptor. Knowledge of coreceptor usage is critical for monitoring disease progression as well as for supporting therapy with the novel drug class of coreceptor antagonists. Predictive methods for inferring coreceptor usage based on the third hypervariable (V3) loop region of the viral gene coding for the envelope protein gp120 can provide us with these monitoring facilities while avoiding expensive phenotypic tests. All simple heuristics (such as the 11/25 rule) as well as statistical learning methods proposed to date predict coreceptor usage based on sequence features of the V3 loop exclusively. Here, we show, based on a recently resolved structure of gp120 with an untruncated V3 loop, that using structural information on the V3 loop in combination with sequence features of V3 variants improves prediction of coreceptor usage. In particular, we propose a distance-based descriptor of the spatial arrangement of physicochemical properties that increases discriminative performance. For a fixed specificity of 0.95, a sensitivity of 0.77 was achieved, improving further to 0.80 when combined with a sequence-based representation using amino acid indicators. This compares favorably with the sensitivities of 0.62 for the traditional 11/25 rule and 0.73 for a prediction based on sequence information as input to a support vector machine and constitutes a statistically significant improvement. A detailed analysis and interpretation of structural features important for classification shows the relevance of several specific hydrogen-bond donor sites and aliphatic side chains to coreceptor specificity towards CCR5 or CXCR4. Furthermore, an analysis of side chain orientation of the specificity-determining residues suggests a major role of one side of the V3 loop in the selection of the coreceptor. The proposed method constitutes the first approach to an improved prediction of coreceptor usage based on an original integration of structural bioinformatics methods with statistical learning.

Dataset Information

Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region.

Publications

Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region.

Similar Datasets

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