Balanced Solvent Model for Intrinsically Disordered and Ordered Proteins.

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 J-coupling and secondary chemical shifts). However, there is still a large deviation for the radius of gyration (Rg). 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 e parameter of the solvent model to play a key role in scaling Rg. A near-linear relationship between the simulation Rg and the e parameter was used to develop the new solvent model, named TIP4P-B. The results indicate that the simulated Rg 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 Rg performance for folded proteins and IDPs.