Exploring the Conformational Space of Growth-Hormone-Releasing Hormone Analogues Using Dopant Assisted Trapped Ion Mobility Spectrometry Mass Spectrometry
Exploring the Conformational Space of Growth-Hormone-Releasing Hormone Analogues Using Dopant Assisted Trapped Ion Mobility Spectrometry Mass Spectrometry
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DOI：
10.1021/acs.jpcb.9b03777
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发表时间：
2019-07-25
影响因子：
3.3
通讯作者：
Fernandez-Lima, Francisco
中科院分区：
文献类型：
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作者：
Fouque, Kevin Jeanne Dit;Moreno, Javier;Fernandez-Lima, Francisco
最近，我们提出了一种高通量筛选工作流程，用于根据结构基序描述符作为起始解决方案的函数来阐明激动性或拮抗性生长激素释放激素（GHRH）的效力。在目前的工作中，我们使用俘获离子淌度质谱 (TIMS-MS) 重新审视了溶液和气相 GHRH 分子微环境的影响。起始溶剂组合物（10 mM 醋酸铵 (NH4Ac)、50% 甲醇 (MeOH)、50% 乙腈 (MeCN) 和 50% 丙酮 (Ac)）和气相改性剂（N-2、N-2 + MeOH、N-2 + MeCN 和 N-2 + Ac）对三种 GHRH 类似物 GHRH (1-29) 构象状态的影响， MR-406 和 MIA-602 被描述为捕获时间 (100-500 ms) 的函数。观察到的迁移率曲线的变化显示了 GHRH 类似物的构象状态与溶液中分子微环境的依赖性，表明溶液记忆效应对气相观察到的结构的存在。改变浴气体成分会导致较小的迁移率，这与有机改性剂的尺寸和质量相关，更重要的是导致 IMS 曲线相对丰度的显着变化。我们将观察到的迁移率变化归因于 GHRH 类似离子和气体改性剂之间的聚类/去聚类机制，重新定义了自由能景观并导致其他局部最小结构。此外，作为捕获时间（100-500 ms）函数的迁移率分布检查允许构象相互转化为更稳定的“气相”结构。这些实验使我们能够更详细地描述 GHRH、MR-406 和 MIA-602 生物活性所涉及的结构和中间体。
Recently, we proposed a high-throughput screening workflow for the elucidation of agonistic or antagonistic growth hormone-releasing hormone (GHRH) potencies based on structural motif descriptors as a function of the starting solution. In the present work, we revisited the influence of solution and gas-phase GHRH molecular microenvironment using trapped ion mobility-mass spectrometry (TIMS-MS). The effect of the starting solvent composition (10 mM ammonium acetate (NH4Ac), 50% methanol (MeOH), 50% acetonitrile (MeCN), and 50% acetone (Ac)) and gas-phase modifiers (N-2, N-2 + MeOH, N-2 + MeCN, and N-2 + Ac) on the conformational states of three GHRH analogues, GHRH (1-29), MR-406, and MIA-602, is described as a function of the trapping time (100-500 ms). Changes in the mobility profiles were observed showing the dependence of the conformational states of GHRH analogues according to the molecular microenvironment in solution, suggesting the presence of solution memory effects on the gas-phase observed structures. Modifying the bath gas composition resulted in smaller mobilities that are correlated with the size and mass of the organic modifier, and more importantly led to substantial changes in relative abundances of the IMS profiles. We attributed the observed changes in the mobility profiles by a clustering/declustering mechanism between the GHRH analogue ions and the gas modifiers, redefining the free energy landscape and leading to other local minima structures. Moreover, inspection of the mobility profiles as a function of the trapping time (100-500 ms) allowed for conformational interconversions toward more stable "gas-phase" structures. These experiments enabled us to outline a more detailed description of the structures and intermediates involved in the biological activity of GHRH, MR-406, and MIA-602.