Accurate Description of Solvent-Exposed Salt Bridges with a Non-polarizable Force Field Incorporating Solvent Effects

The strength of salt bridges resulting from the interaction of cations and anions is modulated by their environment. However, polarization of the solvent molecules by the charged moieties makes the accurate description of cation–anion interactions in an aqueous solution by means of a pairwise additive potential energy function and classical combination rules particularly challenging. In this contribution, aiming at improving the representation of solvent-exposed salt-bridge interactions with an all-atom non-polarizable force field, we put forth here a parametrization strategy. First, the interaction of a cation and an anion is characterized by hybrid quantum mechanical/molecular mechanics (QM/MM) potential of mean force (PMF) calculations, whereby constantly exchanging solvent molecules around the ions are treated at the quantum mechanical level. The Lennard–Jones (LJ) parameters describing the salt-bridge ion pairs are then optimized to match the reference QM/MM PMFs through the so-called nonbonded FIX, or NBFIX, feature of the CHARMM force field. We apply the new set of parameters, coined CHARMM36m-SBFIX, to the calculation of association constants for the ammonium–acetate and guanidinium–acetate complexes, the osmotic pressures for glycine zwitterions, guanidinium, and acetate ions, and to the simulation of both folded and intrinsically disordered proteins. Our findings indicate that CHARMM36m-SBFIX improves the description of solvent-exposed salt-bridge interactions, both structurally and thermodynamically. However, application of this force field to the standard binding free-energy calculation of a protein–ligand complex featuring solvent-excluded salt-bridge interactions leads to a poor reproduction of the experimental value, suggesting that the parameters optimized in an aqueous solution cannot be readily transferred to describe solvent-excluded salt-bridge interactions. Put together, owing to their sensitivity to the environment, modeling salt-bridge interactions by means of a single, universal set of LJ parameters remains a daunting theoretical challenge.阳离子与阴离子相互作用形成的盐桥强度受其所处环境调控。然而，带电基团对溶剂分子的极化作用，使得利用成对加和势能函数与经典组合规则精准描述水溶液中的阴阳离子相互作用，极具挑战性。在本研究中，为了改进全原子不可极化力场对溶剂暴露型盐桥相互作用的表征，我们提出了一套参数化策略。首先，通过混合量子力学/分子力学（QM/MM）平均力势（PMF）计算表征阴阳离子间的相互作用，此时离子周围不断交换的溶剂分子将采用量子力学层面处理。随后，我们借助CHARMM力场的非键相互作用修正（nonbonded FIX，简称NBFIX）功能，优化描述盐桥离子对的伦纳德-琼斯（Lennard-Jones, LJ）参数，使其与参考QM/MM PMF结果相匹配。我们将这套命名为CHARMM36m-SBFIX的全新参数集，应用于乙酸铵与醋酸胍复合物的结合常数计算、甘氨酸两性离子、胍离子及醋酸根离子的渗透压计算，以及折叠蛋白与内在无序蛋白的模拟。研究结果表明，CHARMM36m-SBFIX在结构与热力学层面均优化了对溶剂暴露型盐桥相互作用的描述。然而，将该力场应用于包含溶剂遮蔽型盐桥相互作用的蛋白质-配体复合物标准结合自由能计算时，却无法准确复现实验值，这说明水溶液中优化得到的参数无法直接迁移用于描述溶剂遮蔽型盐桥相互作用。综上，由于盐桥相互作用对环境具有高度敏感性，利用单一通用的LJ参数集对其进行建模，仍是一项极具挑战性的理论难题。