Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS
Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.912518/full |
| _version_ | 1818056196915986432 |
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| author | Jianzhong Chen Shaolong Zhang Qingkai Zeng Wei Wang Qinggang Zhang Xinguo Liu |
| author_facet | Jianzhong Chen Shaolong Zhang Qingkai Zeng Wei Wang Qinggang Zhang Xinguo Liu |
| author_sort | Jianzhong Chen |
| collection | DOAJ |
| description | Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS. |
| first_indexed | 2024-12-10T12:25:00Z |
| format | Article |
| id | doaj.art-293c469ae10149578bb12b90fd17e9c0 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-10T12:25:00Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-293c469ae10149578bb12b90fd17e9c02022-12-22T01:48:58ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-05-01910.3389/fmolb.2022.912518912518Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRASJianzhong Chen0Shaolong Zhang1Qingkai Zeng2Wei Wang3Qinggang Zhang4Xinguo Liu5School of Science, Shandong Jiaotong University, Jinan, ChinaSchool of Physics and Electronics, Shandong Normal University, Jinan, ChinaSchool of Science, Shandong Jiaotong University, Jinan, ChinaSchool of Science, Shandong Jiaotong University, Jinan, ChinaSchool of Physics and Electronics, Shandong Normal University, Jinan, ChinaSchool of Physics and Electronics, Shandong Normal University, Jinan, ChinaMutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS.https://www.frontiersin.org/articles/10.3389/fmolb.2022.912518/fullKRASG12 mutationsMR-GaMD simulationsfree energy profileselectrostatic environment |
| spellingShingle | Jianzhong Chen Shaolong Zhang Qingkai Zeng Wei Wang Qinggang Zhang Xinguo Liu Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS Frontiers in Molecular Biosciences KRAS G12 mutations MR-GaMD simulations free energy profiles electrostatic environment |
| title | Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS |
| title_full | Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS |
| title_fullStr | Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS |
| title_full_unstemmed | Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS |
| title_short | Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS |
| title_sort | free energy profiles relating with conformational transition of the switch domains induced by g12 mutations in gtp bound kras |
| topic | KRAS G12 mutations MR-GaMD simulations free energy profiles electrostatic environment |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.912518/full |
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