Department of Biological Science and Engineering, School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 100083 Beijing , China.
Beijing Key Lab of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology , Box 53, 100029 Beijing , China.
J Chem Inf Model. 2018 Aug 27;58(8):1669-1681. doi: 10.1021/acs.jcim.8b00493. Epub 2018 Aug 10.
The partitioning of amino acids between water and apolar environments is of vital importance in protein function and drug delivery. Here we present an extensive benchmark for octanol/water (log P), chloroform/water (log P), and cyclohexane/water (log P) partition coefficients of neutral amino acid side chain analogues (SCAs) with Amber families of ff99SB-ILDN, ff03, ff14SB, fb15, and ff15ipq, CHARMM 27, GROMOS 53A6, and OPLS-AA/L force fields. A root-mean-square error (RMSE) of 0.4-1.3 log units from experiment is observed for the tested FFs, of which Amber ff94 lineages of ff99SB-ILDN, ff14SB, and fb15 perform best with an RMSE and mean signed error (MSE) of about 0.5 and 0.2 log units, respectively, a performance comparable with quantum mechanical SMD calculations. This finding retains the possibility of modeling proteins in varied environments with one set of classical molecular mechanical force fields. All the FFs tend to overestimate log P, except for GROMOS 53A6 underestimating log P and log P. These discrepancies are mainly due to the larger overestimated solvation free energies in water (Δ G) relative to that in organic solvents (Δ G, Δ G, and Δ G); for GROMOS 53A6, it is due to the underestimated Δ G and Δ G. The latest water models of "FB" and "OPC" families paired with the recent Amber fb15 do not show an obvious improvement for Δ G and log P calculations. The van der Waals interaction between amino acids and cyclohexane is found to be too strong (overestimated) systematically. Scaling protein-water interactions lead to more favorable Δ G, thereby lowering log P and resulting in a better performance for Amber ff03ws, while such scaling seems a bit too much for Amber ff99SBws. This, along with our previous work ( Zhang et al. J. Chem. Inf.
2018 , 58 , 1037 - 1052 ), may aid in the development and systematic improvements of classical force fields to model proteins in aqueous and nonaqueous phases accurately.
氨基酸在水相和非水相环境中的分配对蛋白质功能和药物传递至关重要。在这里，我们提供了广泛的中性氨基酸侧链类似物（SCA）在醇/水（log P）、氯仿/水（log P）和环己烷/水（log P）分配系数的实验基准，这些实验使用 Amber 家族的 ff99SB-ILDN、ff03、ff14SB、fb15 和 ff15ipq、CHARMM 27、GROMOS 53A6 和 OPLS-AA/L 力场进行了测试。结果表明，对于所测试的力场，实验值与计算值的均方根误差（RMSE）在 0.4-1.3 个 log 单位之间，其中 Amber ff94 系列的 ff99SB-ILDN、ff14SB 和 fb15 的 RMSE 和平均符号误差（MSE）分别约为 0.5 和 0.2 log 单位，性能可与量子力学 SMD 计算相媲美。这一发现使我们有可能用一套经典的分子力学力场来模拟不同环境中的蛋白质。所有力场都倾向于高估 log P，除了 GROMOS 53A6 低估了 log P 和 log P。这些差异主要是由于有机溶剂中溶剂化自由能（Δ G）相对于水（Δ G）的相对高估；对于 GROMOS 53A6，则是由于低估了 Δ G 和 Δ G。最新的“FB”和“OPC”家族的水模型与最近的 Amber fb15 配对，对Δ G 和 log P 的计算并没有明显的改进。发现氨基酸与环己烷之间的范德华相互作用系统地过于强烈（高估）。对蛋白质-水相互作用进行缩放会导致更有利的Δ G，从而降低 log P，并使 Amber ff03ws 的性能更好，而对于 Amber ff99SBws，这种缩放似乎有点太多了。这一点，以及我们之前的工作（Zhang 等人，J. Chem. Inf. Model. 2018, 58, 1037-1052），可能有助于开发和系统地改进经典力场，以准确地模拟水相和非水相中的蛋白质。
