{"title":"与G蛋白或阻滞蛋白结合的gpcr中功能水分子的计算研究","authors":"Jiaqi Hu, Xianqiang Sun, Zhengzhong Kang, Jianxin Cheng","doi":"10.1007/s10822-022-00492-z","DOIUrl":null,"url":null,"abstract":"<div><p>G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the α5-helix from G-protein or “finger loop” from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M<sub>2</sub>R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 2","pages":"91 - 105"},"PeriodicalIF":3.0000,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin\",\"authors\":\"Jiaqi Hu, Xianqiang Sun, Zhengzhong Kang, Jianxin Cheng\",\"doi\":\"10.1007/s10822-022-00492-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the α5-helix from G-protein or “finger loop” from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M<sub>2</sub>R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.</p></div>\",\"PeriodicalId\":621,\"journal\":{\"name\":\"Journal of Computer-Aided Molecular Design\",\"volume\":\"37 2\",\"pages\":\"91 - 105\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2022-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Computer-Aided Molecular Design\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10822-022-00492-z\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Computer-Aided Molecular Design","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10822-022-00492-z","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin
G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the α5-helix from G-protein or “finger loop” from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M2R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.
期刊介绍:
The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas:
- theoretical chemistry;
- computational chemistry;
- computer and molecular graphics;
- molecular modeling;
- protein engineering;
- drug design;
- expert systems;
- general structure-property relationships;
- molecular dynamics;
- chemical database development and usage.