Devaurs Didier, Antunes Dinler A, Papanastasiou Malvina, 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 PennsylvaniaPhiladelphia, PA, USA; Broad Institute of MIT & HarvardCambridge, MA, USA.
Front Mol Biosci. 2017 Mar 10;4:13. doi: 10.3389/fmolb.2017.00013. eCollection 2017.
Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis. We show that performing molecular dynamics simulations can be inadequate to obtain such conformations, and we propose a novel methodology involving a coarse-grained conformational sampling approach instead. By extensively exploring the intrinsic flexibility of a protein with this approach, we produce a conformational ensemble from which we extract a conformation providing a good fit to the experimental HDX data. We successfully demonstrate the applicability of our method to four small and medium-sized proteins.
监测溶液中蛋白质发生的氢/氘交换（HDX）会产生实验数据，这些数据可转化为有关蛋白质结构的有价值信息。当有蛋白质的晶体结构时，HDX实验产生的数据通常会根据该晶体结构进行解释。然而，已经表明实验HDX数据与晶体结构之间的对应关系往往并不令人满意。这在尝试对HDX数据进行结构分析时会产生困难。在本文中，我们评估了几种策略，以获得与实验HDX数据高度拟合的构象，这是进行准确结构分析的前提。我们表明，进行分子动力学模拟可能不足以获得此类构象，因此我们提出了一种涉及粗粒度构象采样方法的新方法。通过用这种方法广泛探索蛋白质的内在灵活性，我们生成了一个构象集合，从中提取出与实验HDX数据高度拟合的构象。我们成功地证明了我们的方法对四种中小型蛋白质的适用性。
