Paloncýová Markéta, Fabre Gabin, DeVane Russell H, Trouillas Patrick, Berka Karel, Otyepka Michal
Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc , tř. 17 Listopadu 12, 771 46 Olomouc, Czech Republic.
LCSN EA1069, Faculté de Pharmacie, Université de Limoges , 2 Rue de Docteur Marcland, 87025 Limoges Cedex, France.
J Chem Theory Comput. 2014 Sep 9;10(9):4143-51. doi: 10.1021/ct500419b. Epub 2014 Jul 8.
Studies of drug-membrane interactions witness an ever-growing interest, as penetration, accumulation, and positioning of drugs play a crucial role in drug delivery and metabolism in human body. Molecular dynamics simulations complement nicely experimental measurements and provide us with new insight into drug-membrane interactions; however, the quality of the theoretical data dramatically depends on the quality of the force field used. We calculated the free energy profiles of 11 molecules through a model dimyristoylphosphatidylcholine (DMPC) membrane bilayer using five force fields, namely Berger, Slipids, CHARMM36, GAFFlipids, and GROMOS 43A1-S3. For the sake of comparison, we also employed the semicontinuous tool COSMOmic. High correlation was observed between theoretical and experimental partition coefficients (log K). Partition coefficients calculated by all-atomic force fields (Slipids, CHARMM36, and GAFFlipids) and COSMOmic differed by less than 0.75 log units from the experiment and Slipids emerged as the best performing force field. This work provides the following recommendations (i) for a global, systematic and high throughput thermodynamic evaluations (e.g., log K) of drugs COSMOmic is a tool of choice due to low computational costs; (ii) for studies of the hydrophilic molecules CHARMM36 should be considered; and (iii) for studies of more complex systems, taking into account all pros and cons, Slipids is the force field of choice.
由于药物的渗透、积累和定位在人体药物递送和代谢中起着至关重要的作用，药物与膜相互作用的研究受到越来越多的关注。分子动力学模拟很好地补充了实验测量，并为我们提供了对药物与膜相互作用的新见解；然而，理论数据的质量极大地取决于所使用的力场的质量。我们使用五个力场，即Berger、Slipids、CHARMM36、GAFFlipids和GROMOS 43A1-S3，通过模型二肉豆蔻酰磷脂酰胆碱（DMPC）膜双层计算了11种分子的自由能分布。为了进行比较，我们还使用了半连续工具COSMOmic。理论和实验分配系数（log K）之间观察到高度相关性。由全原子力场（Slipids、CHARMM36和GAFFlipids）和COSMOmic计算的分配系数与实验值的差异小于0.75 log单位，并且Slipids成为表现最佳的力场。这项工作提供了以下建议：（i）对于药物的全局、系统和高通量热力学评估（例如log K），由于计算成本低，COSMOmic是首选工具；（ii）对于亲水分子的研究，应考虑CHARMM36；（iii）对于更复杂系统的研究，综合考虑所有利弊，Slipids是首选力场。
