Many biologically important ligands of proteins are large, flexible, and in many cases charged molecules that bind to extended regions on the protein surface. It is infeasible or expensive to locate such ligands on proteins with standard methods such as docking or molecular dynamics (MD) simulation. The alternative approach proposed here is scanning of a spatial and angular grid around the protein with smaller fragments of the large ligand. Energy values for complete grids can be computed efficiently with a well-known fast Fourier transform-accelerated algorithm and a physically meaningful interaction model. We show that the approach can readily incorporate flexibility of the protein and ligand. The energy grids (EGs) resulting from the ligand fragment scans can be transformed into probability distributions and then directly compared to probability distributions estimated from MD simulations and experimental structural data. We test the approach on a diverse set of complexes between proteins and large, flexible ligands, including a complex of sonic hedgehog protein and heparin, three heparin sulfate substrates or nonsubstrates of an epimerase, a multibranched supramolecular ligand that stabilizes a protein–peptide complex, a flexible zwitterionic ligand that binds to a surface basin of a Kringle domain, and binding of ATP to a flexible site of an ion channel. In all cases, the EG approach gives results that are in good agreement with experimental data or MD simulations.

中文翻译：

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在蛋白质上定位大的柔性配体

蛋白质的许多生物学上重要的配体都是大的，有弹性的，并且在许多情况下，带电分子与蛋白质表面的延伸区域结合。使用标准方法（例如对接或分子动力学（MD）模拟）将此类配体定位在蛋白质上是不可行或昂贵的。本文提出的另一种方法是用大配体的较小片段扫描蛋白质周围的空间和角度网格。可以使用众所周知的快速傅里叶变换加速算法和物理上有意义的交互模型有效地计算出完整网格的能量值。我们表明该方法可以很容易地纳入蛋白质和配体的灵活性。可以将配体片段扫描产生的能量网格（EG）转换为概率分布，然后直接与从MD模拟和实验结构数据估计的概率分布进行比较。我们对蛋白质和大型灵活配体之间的多种复合体进行了测试，包括声波刺猬蛋白和肝素的复合体，差向异构酶的三种硫酸肝素底物或非底物，稳定蛋白质-肽复合物的多支超分子配体，一种柔性的两性离子配体，该配体与Kringle域的表面盆结合，而ATP与离子通道的柔性位点结合。在所有情况下，EG方法所得出的结果都与实验数据或MD模拟非常吻合。