Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee, United States of America.
Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
PLoS One. 2022 May 31;17(5):e0269072. doi: 10.1371/journal.pone.0269072. eCollection 2022.
Water molecules at the protein-small molecule interface often form hydrogen bonds with both the small molecule ligand and the protein, affecting the structural integrity and energetics of a binding event. The inclusion of these 'bridging waters' has been shown to improve the accuracy of predicted docked structures; however, due to increased computational costs, this step is typically omitted in ligand docking simulations. In this study, we introduce a resource-efficient, Rosetta-based protocol named "PlaceWaters" to predict the location of explicit interface bridging waters during a ligand docking simulation. In contrast to other explicit water methods, this protocol is independent of knowledge of number and location of crystallographic waters in homologous structures. We test this method on a diverse protein-small molecule benchmark set in comparison to other Rosetta-based protocols. Our results suggest that this coarse-grained, structure-based approach quickly and accurately predicts the location of bridging waters, improving our ability to computationally screen drug candidates.
蛋白质-小分子界面处的水分子通常与小分子配体和蛋白质形成氢键，影响结合事件的结构完整性和能量学。包含这些“桥接水”已被证明可以提高预测对接结构的准确性；然而，由于计算成本增加，在配体对接模拟中通常会省略这一步骤。在这项研究中，我们引入了一种基于 Rosetta 的资源高效协议，名为“PlaceWaters”，用于在配体对接模拟过程中预测显式界面桥接水的位置。与其他显式水方法不同，该协议不依赖于同源结构中结晶水数量和位置的知识。我们将这种方法与其他基于 Rosetta 的协议在多样化的蛋白质-小分子基准测试集上进行了测试。我们的结果表明，这种粗粒度的基于结构的方法可以快速准确地预测桥接水的位置，提高我们计算筛选药物候选物的能力。
