Dipartimento di Fisica , Università di Cagliari, Cittadella Universitaria , I- 09042 Monserrato (CA) , Italy.
Sorbonne Université , Muséum National d'Histoire Naturelle, UMR CNRS 7590, IRD, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC , F-75005 Paris , France.
J Chem Inf Model. 2019 Apr 22;59(4):1515-1528. doi: 10.1021/acs.jcim.8b00730. Epub 2019 Mar 28.
Understanding molecular recognition of small molecules by proteins in atomistic detail is key for drug design. Molecular docking is a widely used computational method to mimic ligand-protein association in silico. However, predicting conformational changes occurring in proteins upon ligand binding is still a major challenge. Ensemble docking approaches address this issue by considering a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g., molecular dynamics. However, holo structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations called ensemble docking with enhanced sampling of pocket shape (EDES) that allows holo-like conformations of proteins to be generated by exploiting only their apo structures. This is achieved by defining a set of collective variables that effectively sample different shapes of the binding site, ultimately mimicking the steric effect due to the ligand. We assessed the method on three challenging proteins undergoing different extents of conformational changes upon ligand binding. In all cases our protocol generates a significant fraction of structures featuring a low RMSD from the experimental holo geometry. Moreover, ensemble docking calculations using those conformations yielded in all cases native-like poses among the top-ranked ones.
理解蛋白质对小分子的分子识别是药物设计的关键。分子对接是一种广泛使用的计算方法，可以在计算机中模拟配体-蛋白质的结合。然而，预测配体结合时蛋白质发生的构象变化仍然是一个主要挑战。通过考虑从实验或计算机模拟（例如分子动力学）获得的蛋白质的一组不同构象，集合对接方法解决了这个问题。然而，在apo 蛋白的标准分子动力学模拟中，宿主（正确）配体的 holo 结构通常采样不足。为了解决这个限制，我们引入了一种基于元动力学模拟的计算方法，称为口袋形状增强采样的集合对接（EDES），该方法仅利用 apo 结构即可生成类似于 holo 的蛋白质构象。这是通过定义一组有效的采样不同结合位点形状的集体变量来实现的，最终模拟由于配体而产生的空间效应。我们在三个具有不同构象变化程度的挑战性蛋白上评估了该方法。在所有情况下，我们的方案都生成了与实验 holo 几何形状具有低 RMSD 的结构的显著部分。此外，在所有情况下，使用这些构象的集合对接计算都在排名靠前的构象中产生了类似天然的构象。
