Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20814, United States.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
J Chem Theory Comput. 2021 Oct 12;17(10):6240-6261. doi: 10.1021/acs.jctc.1c00550. Epub 2021 Sep 13.
The nonpolarizable CHARMM force field is one of the most widely used energy functions for all-atom biomolecular simulations. Chloride is the only halide ion included in the latest version, CHARMM36m, and is used widely in simulation studies, often as an electrolyte ion but also as the biological substrate of transport proteins and enzymes. Here, we find that existing parameters systematically underestimate the interaction of Cl with proteins and lipids. Accordingly, when examined in solution, little to no Classociation can be observed with most components of the protein, including backbone, polar side chains and aromatic rings. The strength of the interaction with cationic side chains and with alkali ions is also incongruent with experimental measurements, specifically osmotic coefficients of concentrated solutions. Consistent with these findings, a 4-μs trajectory of the Cl-specific transport protein CLC-ec1 shows irreversible Cl dissociation from the so-called S binding site, even in a 150 mM NaCl buffer. To correct for these deficiencies, we formulate a series of pair-specific Lennard-Jones parameters that override those resulting from the conventional Lorentz-Berthelot combination rules. These parameters, referred to as NBFIX, are systematically calibrated against available experimental data as well as ab initio geometry optimizations and energy evaluations, for a wide set of binary and ternary Cl complexes with protein and lipid analogs and alkali cations. Analogously, we also formulate parameter sets for the other three biological halide ions, namely, fluoride, bromide, and iodide. The resulting parameters are used to calculate the potential of mean force defining the interaction of each anion and each of the protein and lipid analogues in bulk water, revealing association free energies in the range of -0.3 to -3.3 kcal/mol, with the F complexes being the least stable. The NBFIX corrections also preserve the Cl occupancy of CLC-ec1 in a second 4-μs trajectory. We posit that these optimized molecular-mechanics models provide a more realistic foundation for all-atom simulation studies of processes entailing changes in hydration, recognition, or transport of halide anions.
非极化 CHARMM 力场是全原子生物分子模拟中使用最广泛的能量函数之一。氯是最新版本 CHARMM36m 中唯一包含的卤化物离子，在模拟研究中被广泛使用，通常作为电解质离子，但也作为转运蛋白和酶的生物底物。在这里，我们发现现有的参数系统地低估了 Cl 与蛋白质和脂质的相互作用。因此，在溶液中，与蛋白质的大多数成分，包括骨架、极性侧链和芳环，几乎没有观察到 Cl 的结合。与阳离子侧链和碱金属离子的相互作用强度也与实验测量值不一致，特别是浓溶液的渗透压系数。与这些发现一致的是，Cl 特异性转运蛋白 CLC-ec1 的 4 μs 轨迹显示 Cl 不可逆地从所谓的 S 结合位点解离，即使在 150 mM NaCl 缓冲液中也是如此。为了纠正这些缺陷，我们制定了一系列对传统 Lorentz-Berthelot 组合规则产生的 Lennard-Jones 参数进行覆盖的对参数。这些参数称为 NBFIX，它们是根据可用的实验数据以及从头算几何优化和能量评估进行系统校准的，校准范围涵盖了与蛋白质和脂质类似物以及碱金属阳离子的广泛的二元和三元 Cl 配合物。类似地，我们还为其他三种生物卤化物离子（即氟化物、溴化物和碘化物）制定了参数集。所得参数用于计算定义每个阴离子与每个蛋白质和脂质类似物在本体水中相互作用的平均力势能，揭示结合自由能在-0.3 至-3.3 kcal/mol 的范围内，其中 F 配合物最不稳定。NBFIX 校正也在第二个 4 μs 轨迹中保留了 CLC-ec1 的 Cl 占有率。我们假设这些优化的分子力学模型为涉及卤化物阴离子水合、识别或转运变化的全原子模拟研究提供了更现实的基础。
