Setny Piotr
Centre of New Technologies, University of Warsaw , Banacha 2c, 02-097 Warsaw, Poland.
J Chem Theory Comput. 2015 Dec 8;11(12):5961-72. doi: 10.1021/acs.jctc.5b00839. Epub 2015 Nov 11.
Buried water molecules are ubiquitous in protein structures and are found at the interface of most protein-ligand complexes. Determining their distribution and thermodynamic effect is a challenging yet important task, of great of practical value for the modeling of biomolecular structures and their interactions. In this study, we present a novel method aimed at the prediction of buried water molecules in protein structures and estimation of their binding free energies. It is based on a semiexplicit, discrete solvation model, which we previously introduced in the context of small molecule hydration. The method is applicable to all macromolecular structures described by a standard all-atom force field, and predicts complete solvent distribution within a single run with modest computational cost. We demonstrate that it indicates positions of buried hydration sites, including those filled by more than one water molecule, and accurately differentiates them from sterically accessible to water but void regions. The obtained estimates of water binding free energies are in fair agreement with reference results determined with the double decoupling method.
埋藏的水分子在蛋白质结构中普遍存在，并且存在于大多数蛋白质-配体复合物的界面处。确定它们的分布和热力学效应是一项具有挑战性但又很重要的任务，对于生物分子结构及其相互作用的建模具有很大的实用价值。在本研究中，我们提出了一种新方法，旨在预测蛋白质结构中埋藏的水分子并估计它们的结合自由能。该方法基于一种半显式、离散溶剂化模型，我们之前在小分子水合作用的背景下引入过该模型。该方法适用于由标准全原子力场描述的所有大分子结构，并且以适度的计算成本在单次运行中预测完整的溶剂分布。我们证明它能指示埋藏水合位点的位置，包括那些被多个水分子占据的位点，并能准确地将它们与对水空间可及但为空的区域区分开来。所获得的水结合自由能估计值与用双去耦方法确定的参考结果相当吻合。
