Practical Guidance for Consensus Scoring and Force Field Selection in Protein-Ligand Binding Free Energy Simulations.
Practical Guidance for Consensus Scoring and Force Field Selection in Protein-Ligand Binding Free Energy Simulations.
复制标题
蛋白质-配体结合自由能模拟中共识评分和力场选择的实用指南。
DOI：
10.1021/acs.jcim.2c01115
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Im,Wonpil
中科院分区：
文献类型：
--
作者：
Zhang,Han;Kim,Seonghoon;Im,Wonpil
配体结合亲和力预测的进展已经通过系统生成工具和改进的力场（FF）得到了促进。CHARMM-GUIFree能量计算器为AMBER-TI自由能计算提供了输入和后处理脚本。在本研究中，我们使用12种不同的FF组合（蛋白质为ff14 SB和ff 19 SB，配体为GAFF2.2和OpenFF，水为TIP 3 P、TIP 4PEW和OPC）来计算80种炼金术转化的相对结合自由能（ΔΔGbind）（在JACS基准集中）具有不同数量的λ窗口（12或21）和模拟时间（1、5或10 ns）。我们的结果表明，12 λ窗口和5 ns的模拟时间为每个窗口是足够的，以获得可靠的ΔΔ Gbind与4个独立的运行为当前的基准集。虽然与实验值相比，12种不同FF组合之间没有统计学上显著的性能差异，但FF 14 SB + GAFF 2.2 + TIP 3 P FF的组合似乎是最佳的，平均无符号误差为0.87 [0.69，1.07] kcal/mol，均方根误差为1.22 [0.94，1.50] kcal/mol，皮尔逊相关系数为0.64 [0.52，0.76]，斯皮尔曼相关系数为0.73 [0.58，0.83]，肯德尔相关系数为0.54 [0.42，0.64]。这项大规模的ΔΔ Gbind计算研究提供了关于不同AMBER FF组合的ΔΔ Gbind预测的有用信息，并为AMBER-TI ΔΔ Gbind计算中FF的选择提供了有价值的建议。
The advances in ligand binding affinity prediction have been fostered by system generation tools and improved force fields (FFs). CHARMM-GUIFree Energy Calculatorprovides input and postprocessing scripts for AMBER-TI free energy calculations with various FFs. In this study, we used 12 different FF combinations (ff14SB and ff19SB for protein, GAFF2.2 and OpenFF for ligand, and TIP3P, TIP4PEW, and OPC for water) to calculate relative binding free energies (ΔΔGbind) for 80 alchemical transformations (among the JACS benchmark set) with different numbers of λ windows (12 or 21) and simulation times (1, 5, or 10 ns). Our results show that 12 λ windows and 5 ns simulation time for each window are sufficient to obtain reliable ΔΔGbindwith 4 independent runs for the current benchmark set. While there is no statistically noticeable performance difference among 12 different FF combinations compared to the experimental values, a combination of ff14SB + GAFF2.2 + TIP3P FFs appears to be best with a mean unsigned error of 0.87 [0.69, 1.07] kcal/mol, a root-mean-square error of 1.22 [0.94, 1.50] kcal/mol, a Pearson’s correlation of 0.64 [0.52, 0.76], a Spearman’s correlation of 0.73 [0.58, 0.83], and a Kendell’s correlation of 0.54 [0.42, 0.64]. This large-scale ΔΔGbindcalculation study provides useful information about ΔΔGbindprediction with different AMBER FF combinations and presents valuable suggestions for FF selection in AMBER-TI ΔΔGbindcalculations.