论文标题
与基于模板的配体构象体选择APO受体的耦合增强的采样：D3R-GC4中的姿势预测性能
Coupling enhanced sampling of the apo-receptor with template-based ligand conformers selection: Performance in pose prediction in the D3R-GC4
论文作者
论文摘要
我们报告了新引入的集合对接的性能，并增强了对基于模板的算法的口袋形状（EDES）协议的采样（EDES）协议，以在2019年D3R联盟组织的大挑战中生成近型的配体构象。使用Autodock4.2或Haddock2.2对接程序（协议的两个变体中的每个软件）我们的方法生成的本机样姿势是在具有类似性能的20个目标中的大多数提交的前5个提交的姿势中。选择的GC4蛋白是人β位点淀粉样蛋白前体蛋白裂解酶1（BACE-1），一种跨膜天冬氨酸蛋白酶。我们发现了至少一个姿势，其重原原子RMSD的使用量分别为16（80％）（80％）和17个（85％）的20个目标，分别使用Autodock和Haddock。解剖可能的错误来源表明：i）我们的EDES协议（次要修改）能够针对所有20种蛋白质靶标进行sub-Ångstrom构象样品，从而重现了〜1ÅRMSD内结合位点的正确构象； ii）正如我们在GC3中已经显示的那样，即使在近蛋白质结构的存在下，适当选择的配体构象异构体对于成功计算的成功至关重要。重要的是，我们的方法在仅利用Apo蛋白的结构信息的方案中表现最好，以生成受体的构象来进行集合船舶计算。
We report the performance of our newly introduced Ensemble Docking with Enhanced sampling of pocket Shape (EDES) protocol coupled to a template-based algorithm to generate near-native ligand conformations in the 2019 iteration of the Grand Challenge organized by the D3R consortium. Using either AutoDock4.2 or HADDOCK2.2 docking programs (each software in two variants of the protocol) our method generated native-like poses among the top 5 submitted for evaluation for most of the 20 targets with similar performances. The protein selected for GC4 was the human beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a transmembrane aspartic-acid protease. We identified at least one pose whose heavy-atoms RMSD was less than 2.5 Å from the native conformation for 16 (80%) and 17 (85%) of the twenty targets using AutoDock and HADDOCK, respectively. Dissecting the possible sources of errors revealed that: i) our EDES protocol (with minor modifications) was able to sample sub-ångstrom conformations for all 20 protein targets, reproducing the correct conformation of the binding site within ~1 Å RMSD; ii) as already shown by some of us in GC3, even in the presence of near-native protein structures, a proper selection of ligand conformers is crucial for the success of ensemble-docking calculations. Importantly, our approach performed best among the protocols exploiting only structural information of the apo protein to generate conformations of the receptor for ensemble-docking calculations.
