Md Fulbabu Sk, Sunanda Samanta, Sayan Poddar, Parimal Kar
{"title":"通过高斯加速分子动力学模拟破解 Janus 激酶 2 抑制的分子编排:动态奥德赛。","authors":"Md Fulbabu Sk, Sunanda Samanta, Sayan Poddar, Parimal Kar","doi":"10.1007/s10822-023-00548-8","DOIUrl":null,"url":null,"abstract":"<div><p>The Janus kinases (JAK) are crucial targets in drug development for several diseases. However, accounting for the impact of possible structural rearrangements on the binding of different kinase inhibitors is complicated by the extensive conformational variability of their catalytic kinase domain (KD). The dynamic KD contains mainly four prominent mobile structural motifs: the phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A-loop) within the C-lobe. These distinct structural orientations imply a complex signal transmission path for regulating the A-loop’s flexibility and conformational preference for optimal JAK function. Nevertheless, the precise dynamical features of the JAK induced by different types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated molecular dynamics simulations in triplicate of three phosphorylated JAK2 systems: the KD alone, type-I ATP-competitive inhibitor (CI) bound KD in the catalytically active DFG<i>-in</i> conformation, and the type-II inhibitor (AI) bound KD in the catalytically inactive DFG-<i>out</i> conformation. Our results indicate significant conformational variations observed in the A-loop and αC helix motions upon inhibitor binding. Our studies also reveal that the DFG-<i>out</i> inactive conformation is characterized by the closed A-loop rearrangement, open catalytic cleft of N and C-lobe, the outward movement of the αC helix, and open P-loop states. Moreover, the outward positioning of the αC helix impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their ligand binding poses and free energy by the MM/PBSA approach. The free energy calculations suggested that the AI’s binding affinity is higher than CI against JAK2 due to an increased favorable contribution from the total non-polar interactions and the involvement of the αC helix. Overall, our study provides the structural and energetic insights crucial for developing more promising type I/II JAK2 inhibitors for treating JAK-related diseases.</p></div>","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey\",\"authors\":\"Md Fulbabu Sk, Sunanda Samanta, Sayan Poddar, Parimal Kar\",\"doi\":\"10.1007/s10822-023-00548-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The Janus kinases (JAK) are crucial targets in drug development for several diseases. However, accounting for the impact of possible structural rearrangements on the binding of different kinase inhibitors is complicated by the extensive conformational variability of their catalytic kinase domain (KD). The dynamic KD contains mainly four prominent mobile structural motifs: the phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A-loop) within the C-lobe. These distinct structural orientations imply a complex signal transmission path for regulating the A-loop’s flexibility and conformational preference for optimal JAK function. Nevertheless, the precise dynamical features of the JAK induced by different types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated molecular dynamics simulations in triplicate of three phosphorylated JAK2 systems: the KD alone, type-I ATP-competitive inhibitor (CI) bound KD in the catalytically active DFG<i>-in</i> conformation, and the type-II inhibitor (AI) bound KD in the catalytically inactive DFG-<i>out</i> conformation. Our results indicate significant conformational variations observed in the A-loop and αC helix motions upon inhibitor binding. Our studies also reveal that the DFG-<i>out</i> inactive conformation is characterized by the closed A-loop rearrangement, open catalytic cleft of N and C-lobe, the outward movement of the αC helix, and open P-loop states. Moreover, the outward positioning of the αC helix impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their ligand binding poses and free energy by the MM/PBSA approach. The free energy calculations suggested that the AI’s binding affinity is higher than CI against JAK2 due to an increased favorable contribution from the total non-polar interactions and the involvement of the αC helix. 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引用次数: 0
摘要
Janus 激酶(JAK)是多种疾病药物开发的关键靶点。然而,由于其催化激酶结构域(KD)具有广泛的构象可变性,因此考虑可能的结构重排对不同激酶抑制剂结合的影响变得非常复杂。动态 KD 主要包含四个突出的移动结构基团:磷酸结合环(P 环)、N 环内的αC-螺旋、Asp-Phe-Gly(DFG)基团和 C 环内的激活环(A 环)。这些不同的结构取向意味着有一个复杂的信号传输路径来调节 A 环的灵活性和构象偏好,以实现最佳的 JAK 功能。尽管如此,不同类型抑制剂诱导的 JAK 的精确动态特征仍然难以捉摸。我们对三个磷酸化的 JAK2 系统进行了一式三份的微秒级高斯加速分子动力学模拟比较:单独的 KD、在催化活性 DFG-in构象中与 I 型 ATP 竞争性抑制剂(CI)结合的 KD 以及在催化不活跃的 DFG-out 构象中与 II 型抑制剂(AI)结合的 KD。我们的研究结果表明,与抑制剂结合后,A 环和αC 螺旋的运动发生了明显的构象变化。我们的研究还发现,DFG-out 非活性构象的特点是闭合的 A 环重排、N 和 C 环的催化裂隙开放、αC 螺旋向外运动以及 P 环开放状态。此外,αC 螺旋的外移还影响了 Lys882 和 Glu898 在非活性构象中形成的标志性盐桥。最后,我们通过 MM/PBSA 方法比较了它们的配体结合位置和自由能。自由能计算表明,AI 与 JAK2 的结合亲和力高于 CI,这是因为总的非极性相互作用和 αC 螺旋的参与增加了有利的贡献。总之,我们的研究为开发更有前景的 I/II 型 JAK2 抑制剂以治疗 JAK 相关疾病提供了至关重要的结构和能量见解。
Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey
The Janus kinases (JAK) are crucial targets in drug development for several diseases. However, accounting for the impact of possible structural rearrangements on the binding of different kinase inhibitors is complicated by the extensive conformational variability of their catalytic kinase domain (KD). The dynamic KD contains mainly four prominent mobile structural motifs: the phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A-loop) within the C-lobe. These distinct structural orientations imply a complex signal transmission path for regulating the A-loop’s flexibility and conformational preference for optimal JAK function. Nevertheless, the precise dynamical features of the JAK induced by different types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated molecular dynamics simulations in triplicate of three phosphorylated JAK2 systems: the KD alone, type-I ATP-competitive inhibitor (CI) bound KD in the catalytically active DFG-in conformation, and the type-II inhibitor (AI) bound KD in the catalytically inactive DFG-out conformation. Our results indicate significant conformational variations observed in the A-loop and αC helix motions upon inhibitor binding. Our studies also reveal that the DFG-out inactive conformation is characterized by the closed A-loop rearrangement, open catalytic cleft of N and C-lobe, the outward movement of the αC helix, and open P-loop states. Moreover, the outward positioning of the αC helix impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their ligand binding poses and free energy by the MM/PBSA approach. The free energy calculations suggested that the AI’s binding affinity is higher than CI against JAK2 due to an increased favorable contribution from the total non-polar interactions and the involvement of the αC helix. Overall, our study provides the structural and energetic insights crucial for developing more promising type I/II JAK2 inhibitors for treating JAK-related diseases.