Sandoval-Perez Angelica, Pluhackova Kristyna, Böckmann Rainer A
Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg , Staudtstrassre 5, 91058 Erlangen, Germany.
J Chem Theory Comput. 2017 May 9;13(5):2310-2321. doi: 10.1021/acs.jctc.7b00001. Epub 2017 Apr 20.
Molecular dynamics (MD) simulations offer the possibility to study biological processes at high spatial and temporal resolution often not reachable by experiments. Corresponding biomolecular force field parameters have been developed for a wide variety of molecules ranging from inorganic ligands and small organic molecules over proteins and lipids to nucleic acids. Force fields have typically been parametrized and validated on thermodynamic observables and structural characteristics of individual compounds, e.g. of soluble proteins or lipid bilayers. Less strictly, due to the added complexity and missing experimental data to compare to, force fields have hardly been tested on the properties of mixed systems, e.g. on protein-lipid systems. Their selection and combination for mixed systems is further complicated by the partially differing parametrization strategies. Additionally, the presence of other compounds in the system may shift the subtle balance of force field parameters. Here, we assessed the protein-lipid interactions as described in the four atomistic force fields GROMOS54a7, CHARMM36 and the two force field combinations Amber14sb/Slipids and Amber14sb/Lipid14. Four observables were compared, focusing on the membrane-water interface: the conservation of the secondary structure of transmembrane proteins, the positioning of transmembrane peptides relative to the lipid bilayer, the insertion depth of side chains of unfolded peptides absorbed at the membrane interface, and the ability to reproduce experimental insertion energies of Wimley-White peptides at the membrane interface. Significant differences between the force fields were observed that affect e.g. membrane insertion depths and tilting of transmembrane peptides.
分子动力学（MD）模拟提供了以高空间和时间分辨率研究生物过程的可能性，而这通常是实验无法达到的。已经为从无机配体和小有机分子到蛋白质、脂质再到核酸等各种各样的分子开发了相应的生物分子力场参数。力场通常是根据单个化合物的热力学观测值和结构特征进行参数化和验证的，例如可溶性蛋白质或脂质双层的特征。不太严格地说，由于混合系统增加了复杂性且缺乏可比较的实验数据，力场几乎没有在混合系统的性质上进行测试，例如蛋白质 - 脂质系统。由于部分不同的参数化策略，它们在混合系统中的选择和组合变得更加复杂。此外，系统中其他化合物的存在可能会改变力场参数的微妙平衡。在这里，我们评估了四种原子力场GROMOS54a7、CHARMM36以及两种力场组合Amber14sb/Slipids和Amber14sb/Lipid14中描述的蛋白质 - 脂质相互作用。比较了四个观测值，重点是膜 - 水界面：跨膜蛋白二级结构的保守性、跨膜肽相对于脂质双层的定位、吸附在膜界面的未折叠肽侧链的插入深度，以及在膜界面重现Wimley - White肽实验插入能量的能力。观察到力场之间存在显著差异，这些差异会影响例如膜插入深度和跨膜肽的倾斜。
