BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal.
J Chem Inf Model. 2021 Jul 26;61(7):3361-3375. doi: 10.1021/acs.jcim.1c00177. Epub 2021 Jun 29.
In force-field methods, the usage of off-center point charges, also called extra points (EPs), is a common strategy to tackle the anisotropy of the electrostatic potential of covalently bonded halogens (X), thus allowing the description of halogen bonds (XBs) at the molecular mechanics/molecular dynamics (MM/MD) level. Diverse EP implementations exist in the literature differing on the charge sets and/or the X-EP distances. Poisson-Boltzmann and surface area (PBSA) calculations can be used to obtain solvation free energies (Δ) of small molecules, often to compute binding free energies (Δ) at the MM-PBSA level. This method depends, among other parameters, on the empirical assignment of atomic radii (PB radii). Given the multiplicity of off-center point-charge models and the lack of specific PB radii for halogens compatible with such implementations, in this work, we assessed the performance of PBSA calculations for the estimation of Δ values in water (Δ), also conducting an optimization of the halogen PB radii (Cl, Br, and I) for each EP model. We not only expand the usage of EP models in the scope of the general AMBER force field (GAFF) but also provide the first optimized halogen PB radii in the context of the CHARMM general force field (CGenFF), thus contributing to improving the description of halogenated compounds in PBSA calculations.
在力场方法中，使用非中心点电荷，也称为额外点（EPs），是解决共价键合卤素（X）的静电势各向异性的常用策略，从而允许在分子力学/分子动力学（MM/MD）水平上描述卤素键（XBs）。文献中存在多种 EP 实现方式，它们在电荷集和/或 X-EP 距离上有所不同。泊松-玻尔兹曼和表面积（PBSA）计算可用于获得小分子的溶剂化自由能（Δ），通常用于在 MM-PBSA 水平上计算结合自由能（Δ）。该方法取决于原子半径（PB 半径）的经验分配等参数。鉴于非中心点电荷模型的多样性以及与这些实现方式兼容的卤素的特定 PB 半径缺乏，在这项工作中，我们评估了 PBSA 计算在水中（Δ）的Δ值估计中的性能，同时还针对每个 EP 模型对卤素 PB 半径（Cl、Br 和 I）进行了优化。我们不仅扩展了 EP 模型在通用 AMBER 力场（GAFF）范围内的使用，还在 CHARMM 通用力场（CGenFF）中提供了第一个优化的卤素 PB 半径，从而有助于提高 PBSA 计算中对卤化化合物的描述。
