Structure Relaxation Approximation (SRA) for Elucidation of Protein Structures from Ion Mobility Measurements
Structure Relaxation Approximation (SRA) for Elucidation of Protein Structures from Ion Mobility Measurements
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DOI：
10.1021/acs.jpcb.8b11818
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发表时间：
2019-04-04
影响因子：
3.3
通讯作者：
Liu, Fanny C.
中科院分区：
文献类型：
--
作者：
Bleiholder, Christian;Liu, Fanny C.
离子迁移谱-质谱法提供了将蛋白质三级和四级结构与其氨基酸序列和翻译后修饰的变化相关联的可能性。然而，由于离子迁移谱测量气相中离子的横截面，因此通过离子迁移谱检测的蛋白质系统的结构通常与其天然溶液结构不同。虽然现在已经确定离子迁移谱通常不能检测蛋白质系统的平衡气相结构，但仍然存在争议的是，检测到的离子的哪些方面（如果有的话）类似于溶液中存在的天然状态。在这里，我们开发的结构弛豫近似（SRA）的方法来预测特定的电荷状态的离子迁移率谱从合奏的解决方案的结构。这使我们能够预测在各种实验条件和电荷状态的实验中观察到的“全局”趋势，从而能够详细的结构解析。SRA预测（实验的RMSD类似于4%），即使是小蛋白泛素在很大程度上保留了其天然的残基间接触与完整的疏水核心时，通过“软”离子迁移率测量研究。由于碰撞激活随着内部自由度的增加而越来越低效，SRA表明离子迁移谱法更有可能基本上保留大于泛素的蛋白质系统的天然状态。
Ion mobility spectrometry-mass spectrometry methods offer the potential to correlate protein tertiary and quaternary structures to variations in their amino acid sequences and post-translational modifications. Because ion mobility spectrometry measures cross sections of ions in the gas phase, however, the structure of protein systems detected by ion mobility spectrometry will generally differ from their native solution structures. While it is now established that ion mobility spectrometry does not typically detect equilibrium gas-phase structures of protein systems, what remains disputed is which aspects, if any, of the detected ions resemble the native state present in solution. Here, we develop the structure relaxation approximation (SRA) method to predict charge-state specific ion mobility spectra from an ensemble of solution structures. This allows us to predict the "global" trends observed in the experiments for various experimental conditions and charge states, thereby enabling detailed structure elucidation. The SRA predicts (RMSD to experiment similar to 4%) that even the small protein ubiquitin largely retains its native inter-residue contacts with an intact hydrophobic core when studied by "soft" ion mobility measurements. Because collisional activation is increasingly inefficient with increasing numbers of internal degrees of freedom, the SRA suggests that it is all the more likely that ion mobility spectrometry retains essentially the native state for protein systems larger than ubiquitin.