Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation.
HIV-1 Gag is a large multidomain poly-protein with flexible unstructured linkers connecting its globular subdomains. It is compact when in solution but assumes an extended conformation when assembled within the immature HIV-1 virion. Here, we use molecular dynamics (MD) simulations to quantitatively...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0221256 |
| _version_ | 1818935247009480704 |
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| author | Chen Lin Paola Mendoza-Espinosa Ioulia Rouzina Orlando Guzmán José Antonio Moreno-Razo Joseph S Francisco Robijn Bruinsma |
| author_facet | Chen Lin Paola Mendoza-Espinosa Ioulia Rouzina Orlando Guzmán José Antonio Moreno-Razo Joseph S Francisco Robijn Bruinsma |
| author_sort | Chen Lin |
| collection | DOAJ |
| description | HIV-1 Gag is a large multidomain poly-protein with flexible unstructured linkers connecting its globular subdomains. It is compact when in solution but assumes an extended conformation when assembled within the immature HIV-1 virion. Here, we use molecular dynamics (MD) simulations to quantitatively characterize the intra-domain interactions of HIV-1 Gag. We find that the matrix (MA) domain and the C-terminal subdomain CActd of the CA capsid domain can form a bound state. The bound state, which is held together primarily by interactions between complementary charged and polar residues, stabilizes the compact state of HIV-1 Gag. We calculate the depth of the attractive free energy potential between the MA/ CActd sites and find it to be about three times larger than the dimerization interaction between the CActd domains. Sequence analysis shows high conservation within the newly-found intra-Gag MA/CActd binding site, as well as its spatial proximity to other well known elements of Gag -such as CActd's SP1 helix region, its inositol hexaphosphate (IP6) binding site and major homology region (MHR), as well as the MA trimerization site. Our results point to a high, but yet undetermined, functional significance of the intra-Gag binding site. Recent biophysical experiments that address the binding specificity of Gag are interpreted in the context of the MA/CActd bound state, suggesting an important role in selective packaging of genomic RNA by Gag. |
| first_indexed | 2024-12-20T05:17:08Z |
| format | Article |
| id | doaj.art-a951eadb458c403d94604cf6f45ec960 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T05:17:08Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a951eadb458c403d94604cf6f45ec9602022-12-21T19:52:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01148e022125610.1371/journal.pone.0221256Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation.Chen LinPaola Mendoza-EspinosaIoulia RouzinaOrlando GuzmánJosé Antonio Moreno-RazoJoseph S FranciscoRobijn BruinsmaHIV-1 Gag is a large multidomain poly-protein with flexible unstructured linkers connecting its globular subdomains. It is compact when in solution but assumes an extended conformation when assembled within the immature HIV-1 virion. Here, we use molecular dynamics (MD) simulations to quantitatively characterize the intra-domain interactions of HIV-1 Gag. We find that the matrix (MA) domain and the C-terminal subdomain CActd of the CA capsid domain can form a bound state. The bound state, which is held together primarily by interactions between complementary charged and polar residues, stabilizes the compact state of HIV-1 Gag. We calculate the depth of the attractive free energy potential between the MA/ CActd sites and find it to be about three times larger than the dimerization interaction between the CActd domains. Sequence analysis shows high conservation within the newly-found intra-Gag MA/CActd binding site, as well as its spatial proximity to other well known elements of Gag -such as CActd's SP1 helix region, its inositol hexaphosphate (IP6) binding site and major homology region (MHR), as well as the MA trimerization site. Our results point to a high, but yet undetermined, functional significance of the intra-Gag binding site. Recent biophysical experiments that address the binding specificity of Gag are interpreted in the context of the MA/CActd bound state, suggesting an important role in selective packaging of genomic RNA by Gag.https://doi.org/10.1371/journal.pone.0221256 |
| spellingShingle | Chen Lin Paola Mendoza-Espinosa Ioulia Rouzina Orlando Guzmán José Antonio Moreno-Razo Joseph S Francisco Robijn Bruinsma Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. PLoS ONE |
| title | Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. |
| title_full | Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. |
| title_fullStr | Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. |
| title_full_unstemmed | Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. |
| title_short | Specific inter-domain interactions stabilize a compact HIV-1 Gag conformation. |
| title_sort | specific inter domain interactions stabilize a compact hiv 1 gag conformation |
| url | https://doi.org/10.1371/journal.pone.0221256 |
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