Comparative analysis of Im7 dynamics with polarizable and non-polarizable CHARMM family of force fields

Electrostatic interactions are fundamental to biomolecular structure, stability, and function. While these interactions are traditionally modeled using fixed-charge force fields, such approaches are not transferable among different molecular environments. Polarizable force fields, such as DRUDE, address this limitation by explicitly incorporating polarization effect. However, their performance does not uniformly surpass that of nonpolarizable force fields, since multiple factors such as bonded terms, dihedral correction maps, and solvent screening also modulate biomolecular dynamics. In this work, we study the Im7 protein to evaluate the structural and dynamic behaviors of non-polarizable (CHARMM36m) and polarizable (DRUDE2019) force fields relative to NMR experiments. Our simulations show that DRUDE better stabilizes α-helices than CHARMM36m, including shorter ones that contain helix-breaking residues. However, both force fields underestimate loop dynamics, particularly in the loop I region, due mainly to restricted dihedral angle sampling. Moreover, salt bridge population and dynamics reveal that DRUDE and CHARMM36m preferentially stabilize different salt-bridges. This variability arises from the interplay of ionic interactions, charge screening by the environment, and the flexibility of neighboring residues. Additionally, the latest DRUDE2019 variant, featuring updated NBFIX and NBTHOLE parameters for ion-protein interactions, demonstrated improved accuracy in modeling Na+-protein interactions. These findings highlight the need to balance bonded and non-bonded interactions along with dihedral correction maps while incorporating polarization effects to improve the accuracy of force fields to model protein structure and dynamics.