Drude2019IDPC polarizable force field reveals structure-function relationship of insulin.

Intrinsically disordered proteins (IDPs) lack stable tertiary structures under physiological conditions, yet play key roles in biological processes and associated with human complex diseases. Their conformational characteristics and high content of charged residues make the use of polarizable force fields an advantageous for simulating IDPs. The Drude2019IDP polarizable force field, previously introduced, has demonstrated comprehensive enhancements and improvements in dipeptides, short peptides, and IDPs, achieving a balanced sampling between IDPs and structured proteins. However, the performance in simulating 5 dipeptides was found to be underestimate. Therefore, we individually performed reweighting and grid-based energy correction map (CMAP) optimization for these 5 dipeptides, resulting in the enhanced Drude2019IDPC force field. The performance of Drude2019IDPC was evaluated with 5 dipeptides, 5 disordered short peptides, and a representative IDP. The results demonstrated a marked improvement comparing with original Drude2019IDP. To further substantiate the capabilities of Drude2019IDPC, MD simulation and Markov state model (MSM) were applied to wild type and mutant for insulin, to elucidate the difference of conformational characteristics and transition path. The findings reveal that mutation can maintain the monomorphic characteristics, providing insights for engineered insulin development. These results indicate that Drude2019IDPC could be used to reveal the structure-function relationship for other proteins.