State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Departments of Molecular Biology and Biochemistry, Chemical Engineering and Materials Science, Biomedical Engineering, University of California, Irvine, California.
Chem Biol Drug Des. 2018 Oct;92(4):1722-1735. doi: 10.1111/cbdd.13342. Epub 2018 Jul 1.
Intrinsically disordered proteins (IDPs) are closely related to various human diseases. Because IDPs lack certain tertiary structure, it is difficult to use X-ray and NMR methods to measure their structures. Therefore, molecular dynamics simulation is a useful tool to study the conformer distribution of IDPs. However, most generic protein force fields were found to be insufficient in simulations of IDPs. Here, we report our development for the CHARMM community. Our residue-specific IDP force field (CHARMM36IDPSFF) was developed based on the base generic force field with CMAP corrections for all 20 naturally occurring amino acids. Multiple tests show that the simulated chemical shifts with the newly developed force field are in quantitative agreement with NMR experiment and are more accurate than the base generic force field. Comparison of J-couplings with previous work shows that CHARMM36IDPSFF and its corresponding base generic force field have their own advantages. In addition, CHARMM36IDPSFF simulations also agree with experiment for SAXS profiles and radii of gyration of IDPs. Detailed analysis shows that CHARMM36IDPSFF can sample more diverse and disordered conformers. These findings confirm that the newly developed force field can improve the balance of accuracy and efficiency for the conformer sampling of IDPs.
无定形蛋白质（IDPs）与各种人类疾病密切相关。由于 IDPs 缺乏某些三级结构，因此难以使用 X 射线和 NMR 方法测量其结构。因此，分子动力学模拟是研究 IDPs 构象分布的有用工具。然而，大多数通用蛋白质力场在 IDPs 的模拟中被发现不足。在这里，我们报告了我们为 CHARMM 社区开发的内容。我们基于基本通用力场，针对所有 20 种天然存在的氨基酸，开发了残基特异性 IDP 力场（CHARMM36IDPSFF）。多项测试表明，使用新开发的力场模拟的化学位移与 NMR 实验定量一致，并且比基本通用力场更准确。与以前的工作相比，J 耦合的比较表明，CHARMM36IDPSFF 和其相应的基本通用力场各有优势。此外，IDPs 的 SAXS 图谱和回转半径的 CHARMM36IDPSFF 模拟也与实验相符。详细分析表明，CHARMM36IDPSFF 可以采样更多样化和无序的构象。这些发现证实了新开发的力场可以提高 IDPs 构象采样的准确性和效率之间的平衡。
