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Effect of Glycosylation on an Immunodominant Region in the V1V2 Variable Domain of the HIV-1 Envelope gp120 Protein
- Source :
- PLoS Computational Biology, PLoS Computational Biology, Vol 12, Iss 10, p e1005094 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Heavy glycosylation of the envelope (Env) surface subunit, gp120, is a key adaptation of HIV-1; however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. Here we explore the patterns of HIV-1 Env gp120 glycosylation, and particularly the enrichment in glycosylation sites proximal to the disulfide linkages at the base of the surface-exposed variable domains. To dissect the influence of glycans on the conformation these regions, we focused on an antigenic peptide fragment from a disulfide bridge-bounded region spanning the V1 and V2 hyper-variable domains of HIV-1 gp120. We used replica exchange molecular dynamics (MD) simulations to investigate how glycosylation influences its conformation and stability. Simulations were performed with and without N-linked glycosylation at two sites that are highly conserved across HIV-1 isolates (N156 and N160); both are contacts for recognition by V1V2-targeted broadly neutralizing antibodies against HIV-1. Glycosylation stabilized the pre-existing conformations of this peptide construct, reduced its propensity to adopt other secondary structures, and provided resistance against thermal unfolding. Simulations performed in the context of the Env trimer also indicated that glycosylation reduces flexibility of the V1V2 region, and provided insight into glycan-glycan interactions in this region. These stabilizing effects were influenced by a combination of factors, including the presence of a disulfide bond between the Cysteines at 131 and 157, which increased the formation of beta-strands. Together, these results provide a mechanism for conservation of disulfide linkage proximal glycosylation adjacent to the variable domains of gp120 and begin to explain how this could be exploited to enhance the immunogenicity of those regions. These studies suggest that glycopeptide immunogens can be designed to stabilize the most relevant Env conformations to focus the immune response on key neutralizing epitopes.<br />Author Summary Heavy glycosylation of the envelope surface subunit, gp120, is a key adaptation of HIV-1, however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. The network of glycans on gp120 is of particular interest with regards to vaccine design, because the glycans both serve as targets for many classes of broadly neutralizing antibodies, and contribute to patterns of immune evasion and escape during HIV-1 infection. In this manuscript, we report on how glycosylation influences an immunogenic but disordered region of gp120. Glycosylation stabilizes the pre-existing conformation, and reduces its propensity to form other secondary structures. It also stabilizes preformed conformation against thermal unfolding. These complementary effects originate from a combination of multiple factors, including the observation that having a glycosylation site adjacent to the disulfide bond further promotes the formation of beta-strand structure in this peptide.
- Subjects :
- 0301 basic medicine
RNA viruses
Glycosylation
Disulfide Linkage
Physiology
Entropy
Glycobiology
Peptide
Plasma protein binding
HIV Envelope Protein gp120
Pathology and Laboratory Medicine
Biochemistry
chemistry.chemical_compound
Immunodeficiency Viruses
Immune Physiology
Medicine and Health Sciences
Biochemical Simulations
Post-Translational Modification
lcsh:QH301-705.5
chemistry.chemical_classification
Immune System Proteins
Ecology
biology
Physics
3. Good health
Molecular Docking Simulation
Computational Theory and Mathematics
Medical Microbiology
Modeling and Simulation
Viral Pathogens
Viruses
Physical Sciences
Disulfide Bonds
Thermodynamics
Antibody
Pathogens
Research Article
Protein Binding
Glycan
Protein subunit
Immunology
Microbiology
Antibodies
03 medical and health sciences
Cellular and Molecular Neuroscience
Protein Domains
Retroviruses
Genetics
Binding site
Antigens
Molecular Biology
Microbial Pathogens
Ecology, Evolution, Behavior and Systematics
Binding Sites
Immunodominant Epitopes
Lentivirus
Organisms
Biology and Life Sciences
Proteins
HIV
Computational Biology
carbohydrates (lipids)
030104 developmental biology
chemistry
lcsh:Biology (General)
Biophysics
biology.protein
HIV-1
Peptides
Single-Chain Antibodies
Subjects
Details
- Language :
- English
- ISSN :
- 15537358 and 1553734X
- Volume :
- 12
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....a82e62f88d36af73e66414dffbfaa64f