A Residue-Resolved Bayesian Approach to Quantitative Interpretation of Hydrogen-Deuterium Exchange from Mass Spectrometry: Application to Characterizing Protein-Ligand Interactions.
A Residue-Resolved Bayesian Approach to Quantitative Interpretation of Hydrogen-Deuterium Exchange from Mass Spectrometry: Application to Characterizing Protein-Ligand Interactions.
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DOI：
10.1021/acs.jpcb.6b09358
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发表时间：
2017-04-20
期刊：
影响因子：
--
通讯作者：
Sali A
中科院分区：
文献类型：
--
作者：
Saltzberg DJ;Broughton HB;Pellarin R;Chalmers MJ;Espada A;Dodge JA;Pascal BD;Griffin PR;Humblet C;Sali A
蛋白质和其他分子之间相互作用的表征对于理解生物系统的作用机制以及药物发现至关重要。绘制这些相互作用的一种越来越有用的方法是使用质谱法（HDX-MS）测量氢/氘交换（HDX），该方法测量通过蛋白质酶消化获得的肽的时间分辨氘掺入。比较载脂蛋白和配体结合条件之间的交换率，得到配体的差异HDX（ΔHDX）图谱。然而，这些数据的残基水平分析必须考虑由于重叠肽引起的实验误差、稀疏性和模糊性。在这里，我们提出了一个贝叶斯方法，包括一个正向模型，噪声模型，先验概率，和蒙特卡洛抽样方案。该方法利用从所有肽同时获得的HDX-MS数据的残基分辨指数速率模型，并明确地模拟实验误差。结果是给定数据的每个残差的ΔHDX幅度和显著性的最佳可能估计。我们通过揭示两种核受体：维生素D受体（VDR）和维甲酸受体γ（RORγ）的ΔHDX数据的更丰富的结构解释来证明该方法。该方法在HDX中实现，并作为开源集成建模平台的独立模块。
Characterization of interactions between proteins and other molecules is crucial for understanding the mechanisms of action of biological systems and, thus, drug discovery. An increasingly useful approach to mapping these interactions is measurement of hydrogen/deuterium exchange (HDX) using mass spectrometry (HDX-MS), which measures the time-resolved deuterium incorporation of peptides obtained by enzymatic digestion of the protein. Comparison of exchange rates between apo- and ligand-bound conditions results in a mapping of the differential HDX (ΔHDX) of the ligand. Residue-level analysis of these data, however, must account for experimental error, sparseness and ambiguity due to overlapping peptides. Here, we propose a Bayesian method consisting of a forward model, noise model, prior probabilities, and a Monte Carlo sampling scheme. This method exploits a residue-resolved exponential rate model of HDX-MS data obtained from all peptides simultaneously, and explicitly models experimental error. The result is the best possible estimate of ΔHDX magnitude and significance for each residue given the data. We demonstrate the method by revealing richer structural interpretation of ΔHDX data on two nuclear receptors: vitamin D-receptor (VDR) and retinoic acid receptor gamma (RORγ). The method is implemented in HDX Workbench and as a standalone module of the open source Integrative Modeling Platform.
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DOI：
10.1007/s13361-012-0373-3
发表时间：
2012-07-01
影响因子：
3.2
作者：
Fajer, Piotr G.;Bou-Assaf, George M.;Marshall, Alan G.
通讯作者：
Marshall, Alan G.
影响因子：
7.4
作者：
Cummins, David J.;Espada, Alfonso;Griffin, Patrick R.
通讯作者：
Griffin, Patrick R.
DOI：
10.1007/978-1-61779-346-2_15
发表时间：
2012-01-01
期刊：
NEISSERIA MENINGITIDIS: ADVANCED METHODS AND PROTOCOLS
影响因子：
--
作者：
Ling, Jessmi M. L.;Silva, Leslie;Schryvers, Anthony B.
通讯作者：
Schryvers, Anthony B.
影响因子：
5.8
作者：
Lobanov, Mikhail Yu;Suvorina, Masha Yu;Galzitskaya, Oxana V.
通讯作者：
Galzitskaya, Oxana V.
影响因子：
3
作者：
Althaus E;Canzar S;Ehrler C;Emmett MR;Karrenbauer A;Marshall AG;Meyer-Bäse A;Tipton JD;Zhang HM
通讯作者：
Zhang HM