Koziara Katarzyna B, Stroet Martin, Malde Alpeshkumar K, Mark Alan E
School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.
J Comput Aided Mol Des. 2014 Mar;28(3):221-33. doi: 10.1007/s10822-014-9713-7. Epub 2014 Jan 30.
To test and validate the Automated force field Topology Builder and Repository (ATB; http://compbio.biosci.uq.edu.au/atb/ ) the hydration free enthalpies for a set of 214 drug-like molecules, including 47 molecules that form part of the SAMPL4 challenge have been estimated using thermodynamic integration and compared to experiment. The calculations were performed using a fully automated protocol that incorporated a dynamic analysis of the convergence and integration error in the selection of intermediate points. The system has been designed and implemented such that hydration free enthalpies can be obtained without manual intervention following the submission of a molecule to the ATB. The overall average unsigned error (AUE) using ATB 2.0 topologies for the complete set of 214 molecules was 6.7 kJ/mol and for molecules within the SAMPL4 7.5 kJ/mol. The root mean square error (RMSE) was 9.5 and 10.0 kJ/mol respectively. However, for molecules containing functional groups that form part of the main GROMOS force field the AUE was 3.4 kJ/mol and the RMSE was 4.0 kJ/mol. This suggests it will be possible to further refine the parameters provided by the ATB based on hydration free enthalpies.
为了测试和验证自动力场拓扑构建器与知识库（ATB；http://compbio.biosci.uq.edu.au/atb/ ），我们使用热力学积分估算了一组214种类药物分子的水合自由焓，其中包括构成SAMPL4挑战一部分的47种分子，并与实验结果进行了比较。计算使用了一种完全自动化的协议，该协议在选择中间点时纳入了对收敛和积分误差的动态分析。该系统的设计和实现使得在将分子提交给ATB后，无需人工干预即可获得水合自由焓。使用ATB 2.0拓扑对214种分子的完整集合计算得到的总体平均无符号误差（AUE）为6.7 kJ/mol，对于SAMPL4中的分子为7.5 kJ/mol。均方根误差（RMSE）分别为9.5和10.0 kJ/mol。然而，对于包含主要GROMOS力场一部分官能团的分子，AUE为3.4 kJ/mol，RMSE为4.0 kJ/mol。这表明基于水合自由焓有可能进一步优化ATB提供的参数。
