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, Lisbon, Portugal.
Phys Chem Chem Phys. 2023 Jul 5;25(26):17535-17546. doi: 10.1039/d2cp04786a.
Halogen bonds (XBs) have become increasingly popular over the past few years with numerous applications in catalysis, material design, anion recognition, and medicinal chemistry. To avoid a rationalization of XB trends, descriptors can be tentatively employed to predict the interaction energy of potential halogen bonds. These typically comprise the electrostatic potential maximum at the tip of the halogen, , or properties based on the topological analysis of the electronic density. However, such descriptors either can only be used with confidence for specific families of halogen bonds or require intense computations and, therefore, are not particularly attractive for large datasets with diverse compounds or biochemical systems. Therefore, the development of a simple, widely applicable, and computationally cheap descriptor remains a challenge as it would facilitate the discovery of new XB applications while also improving the existing ones. Recently, the Intrinsic Bond Strength Index (IBSI) has been proposed as a new tool to evaluate any bond strength, however, it has not been extensively explored in the context of halogen bonding. In this work, we show that IBSI values linearly correlate with the interaction energy of diverse sets of closed-shell halogen-bonded complexes in the ground state, and therefore, can be used to quantitatively predict this property. Although the linear fit models that use quantum-mechanics-based electron density provided MAEs typically below 1 kcal mol, this type of calculation might still be computationally heavy in large sets or systems. Therefore, we also explored the exciting possibility of using a promolecular density approach (IBSI), which only requires the geometry of the complex as an input, being computationally cheap. Surprisingly, the performance was comparable to the QM-based methods, thus opening the door for the usage of IBSI as a fast, yet accurate, XB energy descriptor in large datasets but also in biomolecular systems such as protein-ligand complexes. We also show that the δ descriptor emerging from the Independent Gradient Model that leads to IBSI can be seen as a term proportional to the overlapping van der Waals volume of the atoms at a given interaction distance. Overall, ISBI can be thought of as a complementary descriptor to for situations where the geometry of the complex is available and QM calculations are not feasible whereas the latter still remains a hallmark of XB descriptors.
卤素键（XBs）在过去几年中变得越来越流行，在催化、材料设计、阴离子识别和药物化学等领域有众多应用。为了避免对 XB 趋势进行合理化，人们可以试探性地使用描述符来预测潜在卤素键的相互作用能。这些描述符通常包括卤素尖端的静电势最大值，或者基于电子密度拓扑分析的性质。然而，这些描述符要么只能在特定的卤素键家族中使用，要么需要大量的计算，因此对于包含不同化合物或生化系统的大型数据集来说并不特别有吸引力。因此，开发一种简单、广泛适用且计算成本低廉的描述符仍然是一个挑战，因为它将有助于发现新的 XB 应用，同时也改进现有的应用。最近，提出了内禀键强度指数（IBSI）作为评估任何键强度的新工具，然而，它在卤素键合的背景下还没有得到广泛的探索。在这项工作中，我们表明，IBSI 值与基态下不同的闭壳层卤素键合配合物的相互作用能呈线性相关，因此可以用于定量预测该性质。虽然使用基于量子力学的电子密度的线性拟合模型通常可以将 MAE 控制在 1 kcal/mol 以下，但对于大型数据集或系统，这种计算可能仍然很繁重。因此，我们还探索了使用前分子密度方法（IBSI）的令人兴奋的可能性，该方法只需要复合物的几何形状作为输入，计算成本低廉。令人惊讶的是，该方法的性能与基于 QM 的方法相当，因此为在大型数据集甚至生物分子系统（如蛋白-配体复合物）中使用 IBSI 作为快速而准确的 XB 能量描述符开辟了道路。我们还表明，从独立梯度模型中得出的导致 IBSI 的 δ 描述符可以被视为与给定相互作用距离处原子的重叠范德华体积成比例的项。总的来说，在复合物的几何形状可用且无法进行 QM 计算的情况下，IBSI 可以被视为的补充描述符，而后者仍然是 XB 描述符的标志。
