Solvation Free Energy as a Measure of Hydrophobicity: Application to Serine Protease Binding Interfaces
Solvation Free Energy as a Measure of Hydrophobicity: Application to Serine Protease Binding Interfaces
复制标题
DOI：
10.1021/acs.jctc.9b00742
复制
发表时间：
2019-11-01
影响因子：
5.5
通讯作者：
Liedl, Klaus R.
中科院分区：
文献类型：
--
作者：
Kraml, Johannes;Kamenik, Anna S.;Liedl, Klaus R.
溶剂化和疏水性在多种生物机制中发挥着关键作用。在底物结合以及基于结构的药物设计中，给定蛋白质周围的水分子的热力学性质引起了高度关注。近年来设计的量化水热力学性质的主要算法之一是网格非均匀溶剂化理论（GIST），它在蛋白质周围的网格上计算这些特征。尽管 GIST 具有固有的优势，但计算需求是一个主要缺点，因为较大系统的计算可能需要数天甚至数周的时间。在这里，我们提出了 GIST 算法的 GPU 加速版本，该算法有助于有效估计溶剂化自由能，甚至是大型生物分子界面的溶剂化自由能。此外，我们表明 GIST 可以作为评估蛋白质表面疏水性的可靠工具。我们将该方法应用于一组九种不同的蛋白酶，计算结合界面表面上的局部溶剂化自由能，作为其疏水性的量度。我们发现它们的底物（即肽）的疏水性与结合到结合裂缝中具有令人信服的一致性，因此我们的方法提供了这些生物界面的疏水性特征的可靠描述。
Solvation and hydrophobicity play a key role in a variety of biological mechanisms. In substrate binding, but also in structure-based drug design, the thermodynamic properties of water molecules surrounding a given protein are of high interest. One of the main algorithms devised in recent years to quantify thermodynamic properties of water is the grid inhomogeneous solvation theory (GIST), which calculates these features on a grid surrounding the protein. Despite the inherent advantages of GIST, the computational demand is a major drawback, as calculations for larger systems can take days or even weeks. Here, we present a GPU accelerated version of the GIST algorithm, which facilitates efficient estimates of solvation free energy even of large biomolecular interfaces. Furthermore, we show that GIST can be used as a reliable tool to evaluate protein surface hydrophobicity. We apply the approach on a set of nine different proteases calculating localized solvation free energies on the surface of the binding interfaces as a measure of their hydrophobicity. We find a compelling agreement with the hydrophobicity of their substrates, i.e., peptides, binding into the binding cleft, and thus our approach provides a reliable description of hydrophobicity characteristics of these biological interfaces.