Chongli Geng, Juan Zeng, Xianming Deng, Fei Xia, Xin Xu
{"title":"KRas和CRaf多聚物稳定性的分子动力学研究。","authors":"Chongli Geng, Juan Zeng, Xianming Deng, Fei Xia, Xin Xu","doi":"10.1021/acs.jpcb.4c08767","DOIUrl":null,"url":null,"abstract":"<p><p>In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)<sub>2</sub>·CRaf and (KRas)<sub>2</sub>·(CRaf)<sub>2</sub>, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)<sub>2</sub>·(CRaf)<sub>2</sub> might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"3306-3316"},"PeriodicalIF":2.8000,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes.\",\"authors\":\"Chongli Geng, Juan Zeng, Xianming Deng, Fei Xia, Xin Xu\",\"doi\":\"10.1021/acs.jpcb.4c08767\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)<sub>2</sub>·CRaf and (KRas)<sub>2</sub>·(CRaf)<sub>2</sub>, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)<sub>2</sub>·(CRaf)<sub>2</sub> might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.</p>\",\"PeriodicalId\":60,\"journal\":{\"name\":\"The Journal of Physical Chemistry B\",\"volume\":\" \",\"pages\":\"3306-3316\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-04-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Physical Chemistry B\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jpcb.4c08767\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/3/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Physical Chemistry B","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.jpcb.4c08767","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/24 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes.
In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)2·CRaf and (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)2·(CRaf)2 might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.
期刊介绍：
An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.
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