Polarizable Force Field of Intrinsically Disordered Proteins with CMAP and Reweighting Optimization

Intrinsically disordered proteins (IDPs) are highly structurally heterogeneous without a specific tertiary structure under physiology conditions and play key roles in the development of human diseases. Due to the characteristics of diverse conformations, as one of the important methods, molecular dynamics simulation can complement information for experimental methods. Because of the enrichment for charged amino acids for IDPs, polarizable force fields should be a good choice for the simulation of IDPs. However, current polarizable force fields are limited in sampling conformer features of IDPs. Therefore, a polarizable force field was released and named Drude2019IDP based on Drude2019 with reweighting and grid-based potential energy correction map optimization. In order to evaluate the performance of Drude2019IDP, 16 dipeptides, 18 short peptides, 3 representative IDPs, and 5 structural proteins were simulated. The results show that the NMR observables driven by Drude2019IDP are in better agreement with the experiment data than those by Drude2019 on short peptides and IDPs. Drude2019IDP can sample more diverse conformations than Drude2019. Furthermore, the performances of the two force fields are similar to the sample ordered proteins. These results confirm that the developed Drude2019IDP can improve the reproduction of conformers for intrinsically disordered proteins and can be used to gain insight into the paradigm of sequence disorder for IDPs.

Automated summary

Intrinsically disordered proteins (IDPs) are structurally diverse and play important roles in human diseases. Molecular dynamics simulation complements experimental methods to study IDPs. Current polarizable force fields have limitations in sampling conformers of IDPs. A new polarizable force field, Drude2019IDP, was developed and showed improved performance in reproducing conformers of IDPs.