Biomolecular Simulations Group , Institut Pasteur de Montevideo , Mataojo 2020 , CP 11400 Montevideo , Uruguay.
Shanghai Institute for Advanced Immunochemical Studies , ShanghaiTech University , Shanghai 201210 , China.
J Chem Theory Comput. 2019 Oct 8;15(10):5674-5688. doi: 10.1021/acs.jctc.9b00435. Epub 2019 Sep 5.
The capability to handle highly heterogeneous molecular assemblies in a consistent manner is among the greatest challenges faced when deriving simulation parameters. This is particularly the case for coarse-grained (CG) simulations in which chemical functional groups are lumped into effective interaction centers for which transferability between different chemical environments is not guaranteed. Here, we introduce the parametrization of a set of CG phospholipids compatible with the latest version of the SIRAH force field for proteins. The newly introduced lipid species include different acylic chain lengths and partial unsaturation, as well as polar and acidic head groups that show a very good reproduction of structural membrane determinants, such as areas per lipid, thickness, order parameter, etc., and their dependence with temperature. Simulation of membrane proteins showed unprecedented accuracy in the unbiased description of the thickness-dependent membrane-protein orientation in systems where this information is experimentally available (namely, the SarcoEndoplasmic Reticulum Calcium-SERCA-pump and its regulator Phospholamban). The interactions that lead to this faithful reproduction can be traced down to the single amino acid-lipid interaction level and show full agreement with biochemical data present in the literature. Finally, the present parametrization is implemented in the GROMACS and AMBER simulation packages facilitating its use by a wide portion of the biocomputing community.
以一致的方式处理高度异质的分子组装体是推导模拟参数时面临的最大挑战之一。对于粗粒化 (CG) 模拟来说尤其如此，在这种模拟中，化学官能团被聚集到有效的相互作用中心，而不同化学环境之间的可转移性不能保证。在这里，我们介绍了一组与蛋白质的最新版本 SIRAH 力场兼容的 CG 磷脂的参数化。新引入的脂质种类包括不同的脂酰链长度和部分不饱和性，以及极性和酸性头基，它们很好地再现了结构膜决定因素，如每个脂质的面积、厚度、有序参数等，以及它们与温度的依赖性。在有实验可用信息（即肌浆内质网钙-SERCA-泵及其调节剂肌球蛋白轻链磷酸酶）的系统中，模拟膜蛋白能够以前所未有的精度无偏地描述厚度依赖性的膜蛋白取向。导致这种忠实再现的相互作用可以追溯到单个氨基酸-脂质相互作用的水平，并与文献中存在的生化数据完全一致。最后，目前的参数化已经在 GROMACS 和 AMBER 模拟包中实现，方便了广大生物计算社区的使用。
