{"title":"通过分子动力学模拟研究 GLU283 质子态对 CCR5 构象异质性的影响","authors":"Berna Dogan, Serdar Durdağı","doi":"10.1021/acs.jcim.4c00682","DOIUrl":null,"url":null,"abstract":"<p><p>CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor's <i>apo</i> form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU283<sup>7.39</sup> in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU283<sup>7.39</sup> caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU283<sup>7.39</sup> was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU283<sup>7.39</sup>. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using <i>in silico</i> methods such as molecular docking, as it may be necessary to consider the protonated state of GLU283<sup>7.39</sup>.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":"8283-8298"},"PeriodicalIF":5.6000,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations.\",\"authors\":\"Berna Dogan, Serdar Durdağı\",\"doi\":\"10.1021/acs.jcim.4c00682\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor's <i>apo</i> form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU283<sup>7.39</sup> in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU283<sup>7.39</sup> caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU283<sup>7.39</sup> was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU283<sup>7.39</sup>. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using <i>in silico</i> methods such as molecular docking, as it may be necessary to consider the protonated state of GLU283<sup>7.39</sup>.</p>\",\"PeriodicalId\":44,\"journal\":{\"name\":\"Journal of Chemical Information and Modeling \",\"volume\":\" \",\"pages\":\"8283-8298\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-11-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Information and Modeling \",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jcim.4c00682\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/22 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Information and Modeling ","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.jcim.4c00682","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations.
CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor's apo form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU2837.39 in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU2837.39 caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU2837.39 was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU2837.39. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using in silico methods such as molecular docking, as it may be necessary to consider the protonated state of GLU2837.39.
期刊介绍:
The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery.
Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field.
As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.