Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease
HIV-2 protease (PR2) is a homodimer targeted by drugs in the treatment of HIV-2 infections. This dimer is often considered symmetric. However, exploration of crystallographic structures showed that the two chains of PR2 exhibit different conformations. This study presents the first analysis of the s...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Symmetry |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-8994/14/2/362 |
| _version_ | 1797476428905709568 |
|---|---|
| author | Anne Badel Laëtitia Breuil Pierre Laville Leslie Regad |
| author_facet | Anne Badel Laëtitia Breuil Pierre Laville Leslie Regad |
| author_sort | Anne Badel |
| collection | DOAJ |
| description | HIV-2 protease (PR2) is a homodimer targeted by drugs in the treatment of HIV-2 infections. This dimer is often considered symmetric. However, exploration of crystallographic structures showed that the two chains of PR2 exhibit different conformations. This study presents the first analysis of the structural asymmetry of PR2 induced by its intrinsic flexibility. We followed the structural asymmetry of PR2 throughout a molecular dynamics (MD) simulation of 1 microsecond. To do so, we quantified the global and local structural asymmetries of 1001 structures extracted from the MD simulation using the root mean square deviation (RMSD) between the two chains in each structure. We then analyzed the links between global and local asymmetry and PR2 flexibility. Our results showed that the global asymmetry of PR2 evolves over time and that it is not explained by the asymmetry of only one region of PR2. We noted that the most flexible regions of PR2 are the most asymmetric regions, revealing that the structural asymmetry of a region is induced by its intrinsic flexibility. Using multivariate analysis methods, we identified six asymmetric profiles varying from structures exhibiting weak asymmetry to structures with extreme asymmetry in at least eight different regions. The analysis of transitions between the different profiles in the MD simulation showed that two consecutive structures often exhibit similar asymmetric profiles, revealing small deformations. To conclude, this study provides insights which help to better understand PR2’s structure, dynamics, and deformations. |
| first_indexed | 2024-03-09T20:57:41Z |
| format | Article |
| id | doaj.art-a4608ca41b964d618915b29a172733c5 |
| institution | Directory Open Access Journal |
| issn | 2073-8994 |
| language | English |
| last_indexed | 2024-03-09T20:57:41Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Symmetry |
| spelling | doaj.art-a4608ca41b964d618915b29a172733c52023-11-23T22:17:21ZengMDPI AGSymmetry2073-89942022-02-0114236210.3390/sym14020362Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 ProteaseAnne Badel0Laëtitia Breuil1Pierre Laville2Leslie Regad3Unité de Biologie Fonctionnelle et Adaptative, INSERM, CNRS, Université de Paris, F-75013 Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, INSERM, CNRS, Université de Paris, F-75013 Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, INSERM, CNRS, Université de Paris, F-75013 Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, INSERM, CNRS, Université de Paris, F-75013 Paris, FranceHIV-2 protease (PR2) is a homodimer targeted by drugs in the treatment of HIV-2 infections. This dimer is often considered symmetric. However, exploration of crystallographic structures showed that the two chains of PR2 exhibit different conformations. This study presents the first analysis of the structural asymmetry of PR2 induced by its intrinsic flexibility. We followed the structural asymmetry of PR2 throughout a molecular dynamics (MD) simulation of 1 microsecond. To do so, we quantified the global and local structural asymmetries of 1001 structures extracted from the MD simulation using the root mean square deviation (RMSD) between the two chains in each structure. We then analyzed the links between global and local asymmetry and PR2 flexibility. Our results showed that the global asymmetry of PR2 evolves over time and that it is not explained by the asymmetry of only one region of PR2. We noted that the most flexible regions of PR2 are the most asymmetric regions, revealing that the structural asymmetry of a region is induced by its intrinsic flexibility. Using multivariate analysis methods, we identified six asymmetric profiles varying from structures exhibiting weak asymmetry to structures with extreme asymmetry in at least eight different regions. The analysis of transitions between the different profiles in the MD simulation showed that two consecutive structures often exhibit similar asymmetric profiles, revealing small deformations. To conclude, this study provides insights which help to better understand PR2’s structure, dynamics, and deformations.https://www.mdpi.com/2073-8994/14/2/362HIV-2 proteasestructural asymmetryintrinsic flexibilitymolecular dynamics simulation |
| spellingShingle | Anne Badel Laëtitia Breuil Pierre Laville Leslie Regad Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease Symmetry HIV-2 protease structural asymmetry intrinsic flexibility molecular dynamics simulation |
| title | Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease |
| title_full | Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease |
| title_fullStr | Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease |
| title_full_unstemmed | Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease |
| title_short | Exploration of the Structural Asymmetry Induced by the Intrinsic Flexibility of HIV-2 Protease |
| title_sort | exploration of the structural asymmetry induced by the intrinsic flexibility of hiv 2 protease |
| topic | HIV-2 protease structural asymmetry intrinsic flexibility molecular dynamics simulation |
| url | https://www.mdpi.com/2073-8994/14/2/362 |
| work_keys_str_mv | AT annebadel explorationofthestructuralasymmetryinducedbytheintrinsicflexibilityofhiv2protease AT laetitiabreuil explorationofthestructuralasymmetryinducedbytheintrinsicflexibilityofhiv2protease AT pierrelaville explorationofthestructuralasymmetryinducedbytheintrinsicflexibilityofhiv2protease AT leslieregad explorationofthestructuralasymmetryinducedbytheintrinsicflexibilityofhiv2protease |