Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation
The KRASG12C mutant is often associated with human cancers, and AMG 510 as a promising covalent inhibitor of KRASG12C has achieved surprising efficacy in clinical trials. However, the interaction mechanism between KRASG12C and AMG 510 is not completely understood. Here, we performed all-atom molecul...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022000587 |
| _version_ | 1828088084138295296 |
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| author | Yu Li Lei Han Ziding Zhang |
| author_facet | Yu Li Lei Han Ziding Zhang |
| author_sort | Yu Li |
| collection | DOAJ |
| description | The KRASG12C mutant is often associated with human cancers, and AMG 510 as a promising covalent inhibitor of KRASG12C has achieved surprising efficacy in clinical trials. However, the interaction mechanism between KRASG12C and AMG 510 is not completely understood. Here, we performed all-atom molecular dynamics simulations on the complex of KRASG12C-AMG 510 to explore the influence of this covalent inhibitor on the conformational change of KRASG12C. A PCA (Principal Component Analysis) model was constructed based on known KRAS crystal structures to distinguish different conformations (active, inactive, and other). By mapping simulation trajectories onto the PCA model, we observed that the conformations of KRASG12C bound with AMG 510 were mainly concentrated in the inactive conformation. Further analysis demonstrated that AMG 510 reduced the flexibility of two switch regions to make the complex of KRASG12C-AMG 510 restricted in the inactive conformation. In the meantime, we also identified key interacting residues between KRASG12C and AMG 510 through the calculation of binding energy. Finally, we built a series of KRAS second-site mutation systems (i.e. KRASG12C/mutations) to conduct large-scale screening of potential resistance mutations. By further combining MD simulations and the PCA model, we not only recapitulated the currently known resistance mutations of AMG 510 successfully but also proposed some novel potential resistant mutations. Taken together, these results broaden our insight into the influence of AMG 510 on the conformational change of the KRASG12C mutant at the atomic level, thereby providing crucial hints for the improvement and optimization of drug candidates. |
| first_indexed | 2024-04-11T05:20:45Z |
| format | Article |
| id | doaj.art-f766fec56ed64b3e8c006c949c7643f0 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:45Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-f766fec56ed64b3e8c006c949c7643f02022-12-24T04:51:33ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012010561067Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulationYu Li0Lei Han1Ziding Zhang2State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, ChinaCancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Corresponding authors at: Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China (L. Han); State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China (Z. Zhang).State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China; Corresponding authors at: Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China (L. Han); State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China (Z. Zhang).The KRASG12C mutant is often associated with human cancers, and AMG 510 as a promising covalent inhibitor of KRASG12C has achieved surprising efficacy in clinical trials. However, the interaction mechanism between KRASG12C and AMG 510 is not completely understood. Here, we performed all-atom molecular dynamics simulations on the complex of KRASG12C-AMG 510 to explore the influence of this covalent inhibitor on the conformational change of KRASG12C. A PCA (Principal Component Analysis) model was constructed based on known KRAS crystal structures to distinguish different conformations (active, inactive, and other). By mapping simulation trajectories onto the PCA model, we observed that the conformations of KRASG12C bound with AMG 510 were mainly concentrated in the inactive conformation. Further analysis demonstrated that AMG 510 reduced the flexibility of two switch regions to make the complex of KRASG12C-AMG 510 restricted in the inactive conformation. In the meantime, we also identified key interacting residues between KRASG12C and AMG 510 through the calculation of binding energy. Finally, we built a series of KRAS second-site mutation systems (i.e. KRASG12C/mutations) to conduct large-scale screening of potential resistance mutations. By further combining MD simulations and the PCA model, we not only recapitulated the currently known resistance mutations of AMG 510 successfully but also proposed some novel potential resistant mutations. Taken together, these results broaden our insight into the influence of AMG 510 on the conformational change of the KRASG12C mutant at the atomic level, thereby providing crucial hints for the improvement and optimization of drug candidates.http://www.sciencedirect.com/science/article/pii/S2001037022000587KRASG12CAMG 510Molecular dynamic simulationPrincipal component analysisResistant mutation |
| spellingShingle | Yu Li Lei Han Ziding Zhang Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation Computational and Structural Biotechnology Journal KRASG12C AMG 510 Molecular dynamic simulation Principal component analysis Resistant mutation |
| title | Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation |
| title_full | Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation |
| title_fullStr | Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation |
| title_full_unstemmed | Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation |
| title_short | Understanding the influence of AMG 510 on the structure of KRASG12C empowered by molecular dynamics simulation |
| title_sort | understanding the influence of amg 510 on the structure of krasg12c empowered by molecular dynamics simulation |
| topic | KRASG12C AMG 510 Molecular dynamic simulation Principal component analysis Resistant mutation |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022000587 |
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