Devaurs Didier, Papanastasiou Malvina, Antunes Dinler A, Abella Jayvee R, Moll Mark, Ricklin Daniel, Lambris John D, Kavraki Lydia E
Department of Computer Science, Rice University, Houston, TX, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Int J Comput Biol Drug Des. 2018;11(1-2):90-113. doi: 10.1504/IJCBDD.2018.090834. Epub 2018 Mar 24.
Hydrogen/deuterium exchange detected by mass spectrometry (HDXMS) provides valuable information on protein structure and dynamics. Although HDX-MS data is often interpreted using crystal structures, it was suggested that conformational ensembles produced by molecular dynamics simulations yield more accurate interpretations. In this paper, we analyse the complement protein C3d by performing an HDX-MS experiment, and evaluate several interpretation methodologies using an existing prediction model to derive HDX-MS data from protein structure. To interpret and refine C3d's HDX-MS data, we look for a conformation (or conformational ensemble) of C3d that allows computationally replicating this data. We confirm that crystal structures are not a good choice and suggest that conformational ensembles produced by molecular dynamics simulations might not always be satisfactory either. Finally, we show that coarse-grained conformational sampling of C3d produces a conformation from which its HDX-MS data can be replicated and refined.
通过质谱检测的氢/氘交换（HDXMS）可提供有关蛋白质结构和动力学的有价值信息。尽管HDX-MS数据通常使用晶体结构进行解释，但有人认为分子动力学模拟产生的构象集合能给出更准确的解释。在本文中，我们通过进行HDX-MS实验分析补体蛋白C3d，并使用现有的预测模型从蛋白质结构推导HDX-MS数据来评估几种解释方法。为了解释和完善C3d的HDX-MS数据，我们寻找一种C3d的构象（或构象集合），使其能够通过计算复制此数据。我们证实晶体结构不是一个好的选择，并表明分子动力学模拟产生的构象集合也并非总是令人满意。最后，我们表明对C3d进行粗粒度构象采样可产生一种构象，从中可以复制和完善其HDX-MS数据。
