Tackling Halogenated Species with PBSA: Effect of Emulating the σ‑Hole

To model halogen-bond phenomena using
classical force fields, an
extra point (EP) of charge is frequently introduced at a given distance
from the halogen (X) to emulate the σ-hole. The resulting molecular
dynamics (MD) trajectories can be used in subsequent molecular mechanics
(MM) combined with Poisson–Boltzmann and surface area calculations
(PBSA) to estimate protein–ligand binding free energies (ΔGbind). While EP addition improves the MM/MD
description of halogen-containing systems, its effect on the calculation
of solvation free energies (ΔGsolv) using the PBSA approach is yet to be assessed. As the PBSA calculations
depend, among other parameters, on the empirical assignment of radii
(PB radii), a problematic issue arises, since standard halogen radii
are smaller than the typical X···EP distances, thus
placing the EP within the solvent dielectric. Herein, we took a common
literature EP parametrization scheme, which uses X···EP
= Rmin and RESP charges in the context
of GAFF, and performed a comprehensive study on the performance of
PBSA (using three different setups) in the calculation of ΔGsolv values for 142 halogenated compounds (bearing
Cl, Br, or I) for which the experimental values are known. By conducting
an optimization (minimizing the error against experimental values),
we provide a new optimized set of halogen PB radii, for each PBSA
setup, that should be used in the context of the aforementioned scenario.
A simultaneous optimization of PB radii and X···EP
distances shows that a wide range of distance/radius pairs can be
used without significant loss of accuracy, therefore laying the basis
for expanding this halogen radii optimization strategy to other force
fields and EP implementations. As ligand ΔGsolv estimation is an important term in the determination
of protein–ligand ΔGbind,
this work is particularly relevant in the framework of structure-based
virtual screening and related computer-aided drug design routines.

为模拟卤素键现象，通常在卤素（X）的特定距离处引入一个额外的电荷点（EP），以模拟σ空穴。由此产生的分子动力学（MD）轨迹可以用于后续的分子力学（MM）计算，并结合泊松-玻尔兹曼和表面积计算（PBSA）来估算蛋白质-配体结合自由能（ΔGbind）。尽管EP的添加改善了含有卤素的系统的MM/MD描述，但其对使用PBSA方法计算溶剂化自由能（ΔGsolv）的影响尚未得到评估。由于PBSA计算依赖于多种参数，包括经验的半径分配（PB半径），因此出现了一个问题，因为标准卤素半径小于典型的X···EP距离，从而导致EP位于溶剂介电常数内。在本研究中，我们采用了文献中常见的EP参数化方案，该方案在GAFF的背景下使用X···EP = Rmin和RESP电荷，并对三种不同设置下的PBSA在计算142个已知实验值的卤素化合物的ΔGsolv值方面的性能进行了全面研究。通过优化（最小化与实验值的误差），我们提供了一组新的优化卤素PB半径，适用于上述场景下的每个PBSA设置。PB半径和X···EP距离的同时优化表明，广泛的距离/半径对可以用于而不显著降低准确性，因此为将此卤素半径优化策略扩展到其他力场和EP实现奠定了基础。由于配体ΔGsolv估计是确定蛋白质-配体ΔGbind的重要参数，因此这项工作在基于结构的虚拟筛选和相关计算机辅助药物设计流程的框架中尤其相关。