State Key Laboratory of Microbial metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
MD Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
J Chem Inf Model. 2021 Oct 25;61(10):5141-5151. doi: 10.1021/acs.jcim.1c00407. Epub 2021 Sep 21.
Intrinsically disordered proteins (IDPs) have no fixed three-dimensional (3D) structures under physiological conditions, with the content being about 51% in human proteomics. IDPs are associated with many human diseases, such as cancer, diabetes, and neurodegenerative diseases. Because IDPs do not crystallize and have diverse conformers, traditional experimental methods such as crystallization and NMR can hardly capture their conformation ensemble and just provide average structural characters of IDPs. Therefore, molecular dynamics (MD) simulations become a valuable complement to the experimental data. However, the accuracy of molecular dynamics simulation for IDPs depends on the combination of force fields and solvent models. Recently, we released an environment-specific force field (ESFF1) for IDPs, which can well reproduce the local structural properties (such as -coupling and secondary chemical shifts). However, there is still a large deviation for the radius of gyration (). Therefore, a solvent model combined with ESFF1 is necessary to capture the local and global characters for IDPs and ordered proteins. Here, we investigated the underestimation or overestimation of the solvent interaction for four solvent models (TIP3P, TIP4P-Ew, TIP4P-D, OPC) under ESFF1 and found the important ε parameter of the solvent model to play a key role in scaling . A near-linear relationship between the simulation and the ε parameter was used to develop the new solvent model, named TIP4P-B. The results indicate that the simulated with TIP4P-B is in better agreement with the experimental observations than the other four solvent models. Simultaneously, TIP4P-B can also maintain the advantages of the ESFF1 force field for the local structural properties. Additionally, TIP4P-B can successfully sample the conformation of ordered proteins. These findings confirm that TIP4P-B is a balanced solvent model and can improve sampling performance for folded proteins and IDPs.
无定形蛋白质（IDPs）在生理条件下没有固定的三维（3D）结构，其含量约占人类蛋白质组学的 51%。IDPs 与许多人类疾病有关，如癌症、糖尿病和神经退行性疾病。由于 IDPs 不会结晶且具有多种构象，传统的实验方法（如结晶和 NMR）很难捕捉到它们的构象组合，只能提供 IDPs 的平均结构特征。因此，分子动力学（MD）模拟成为实验数据的有价值补充。然而，IDPs 的分子动力学模拟的准确性取决于力场和溶剂模型的组合。最近，我们发布了一种特定环境的力场（ESFF1）用于 IDPs，它可以很好地再现局部结构特性（如 -耦合和二级化学位移）。然而，对于回转半径（）仍然存在较大偏差。因此，需要结合 ESFF1 的溶剂模型来捕捉 IDPs 和有序蛋白质的局部和全局特征。在这里，我们研究了四种溶剂模型（TIP3P、TIP4P-Ew、TIP4P-D、OPC）在 ESFF1 下对溶剂相互作用的低估或高估，发现溶剂模型的重要 ε 参数在缩放 方面起着关键作用。我们使用模拟的 与 ε 参数之间的近似线性关系来开发新的溶剂模型，命名为 TIP4P-B。结果表明，与其他四种溶剂模型相比，TIP4P-B 模拟的 与实验观察结果更吻合。同时，TIP4P-B 也可以保持 ESFF1 力场在局部结构特性方面的优势。此外，TIP4P-B 可以成功地对有序蛋白质的构象进行采样。这些发现证实了 TIP4P-B 是一种平衡的溶剂模型，可以提高折叠蛋白质和 IDPs 的采样 性能。
