Fortuna Andreia, Costa Paulo J
BioISI─Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Lisboa 1749-016, Portugal.
Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa 1749-016, Portugal.
J Chem Inf Model. 2023 Dec 11;63(23):7464-7475. doi: 10.1021/acs.jcim.3c01561. Epub 2023 Nov 27.
Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (Δ), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict Δ values. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the Δ when compared with the models without EP, especially for the chlorinated compounds; however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds. We also highlight the importance of the choice of the EP model, especially for the iodinated molecules, since a slight tendency to improve the prediction is observed for compounds with a larger σ-hole but significantly worse results were obtained for compounds that are weaker XB donors.
含卤素的化合物因其各向异性静电势可与蛋白质和膜等生物靶点形成卤键（XB）。为准确描述这种各向异性，非中心点电荷（EP）模型常用于力场方法中，以便在分子力学和分子动力学水平描述卤键。文献中已记录了各种EP实现方式，尽管它们在重现蛋白质 - 配体几何结构和卤键采样方面很有效，但尚不清楚这些EP模型对诸如水化自由能（Δ）等实验性质的预测效果如何，而水化自由能常用于验证力场性能。在这项工作中，我们报告了首次使用炼金术自由能计算对三种EP模型预测Δ值的评估。我们表明，与无EP的模型相比，使用某些EP模型描述卤素各向异性在预测Δ时可带来轻微改善，特别是对于氯化化合物；然而，这种改善与卤键的形成无关，很可能是由于氢键采样的改善。我们还强调了EP模型选择的重要性，特别是对于碘化分子，因为对于具有较大σ - 空穴的化合物观察到有轻微的预测改善趋势，但对于较弱的XB供体化合物则得到明显更差的结果。
