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首页> 外文期刊>Biochemistry >Challenges in the Interpretation of Protein H/D Exchange Data: A Molecular Dynamics Simulation Perspective
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Challenges in the Interpretation of Protein H/D Exchange Data: A Molecular Dynamics Simulation Perspective

机译：蛋白质H / D交换数据解释中的挑战：分子动力学模拟的观点

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Many protein structural investigations involve the use of H/D exchange (HDX) techniques. It is commonly thought that amide backbone protection arises from intramolecular H-bonding and/or burial of NH sites. Recently, fundamental HDX-related tenets have been called into question. The current work focuses on ubiquitin for exploring the defining features that distinguish amides in open (exchange-competent) and closed (exchange-incompetent) environments. Instead of relying on static X-ray structures, we employ all-atom molecular dynamics (MD) simulations for obtaining a dynamic view of the protein ground state and its surrounding solvent. The HDX properties for 57 out of 72 NH sites can be readily explained on the basis of backbone and side chain H-bonding, as well as solvent accessibility considerations. Unexpectedly, the same criteria fail for predicting the HDX characteristics of the remaining 15 amides. Significant protection is seen for numerous exposed NH sites that are not engaged in intramolecular H-bonds, whereas other amides that seemingly share the same features are unprotected. We scrutinize the proposal that H-bonding to crystallographically defined water can cause the protection of surface amides. For ubiquitin, the positioning of crystal water is not compatible with this idea. To further explore possible solvation effects, we tested for the presence of partially immobilized water networks. Our MD data reveal no difference in the solvation properties of protected vs unprotected surface amides, making it unlikely that restricted water dynamics can cause anomalous amide protection. The findings reported here suggest that efforts to deduce protein structural features on the basis of HDX protection factors may yield misleading results. This conclusion is relevant for initiatives that rely on sparse structural data as constraints for elucidating protein conformations. It may be necessary to pursue detailed quantum mechanical studies of the protein, the solvent, and the hydroxide catalyst for obtaining a comprehensive understanding of the factors that govern HDX rates. The considerable size of the systems involved makes such endeavors a daunting task.
机译：许多蛋白质结构研究涉及H / D交换（HDX）技术的使用。通常认为酰胺主链保护起因于分子内的H键和/或埋藏NH位。最近，有关HDX的基本原则受到质疑。当前的工作集中在泛素上，以探索在开放（可交换）和封闭（不可交换）环境中区分酰胺的定义特征。我们不依赖静态X射线结构，而是使用全原子分子动力学（MD）模拟来获得蛋白质基态及其周围溶剂的动态视图。基于主链和侧链的H键以及溶剂可及性的考虑，可以轻松解释72个NH位中57个的HDX性质。出乎意料的是，相同的标准无法预测其余15种酰胺的HDX特性。对于许多未参与分子内氢键的暴露的NH位点，可以看到显着的保护作用，而看似具有相同特征的其他酰胺则不受保护。我们仔细研究了将H键键合到结晶学定义的水上可以引起表面酰胺保护的提议。对于泛素，结晶水的定位与此想法不符。为了进一步探索可能的溶剂化作用，我们测试了部分固定的水网络的存在。我们的MD数据显示，受保护的和未保护的表面酰胺的溶剂化特性没有差异，因此受限制的水动力学不太可能导致酰胺保护异常。此处报道的发现表明，根据HDX保护因子推论蛋白质结构特征的努力可能会产生误导性的结果。该结论与依赖稀疏结构数据作为阐明蛋白质构象的限制的倡议有关。为了全面了解控制HDX速率的因素，可能有必要对蛋白质，溶剂和氢氧化物催化剂进行详细的量子力学研究。所涉及系统的相当大的规模使得这种努力成为艰巨的任务。

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