(258b) Balancing Divalent Ion-Biomolecular Interactions in the Polarizable Drude Force Field

The progress in polarizable force fields has the potential to surpass the limitations of traditional additive force fields, particularly in systems with high ionic concentrations and intricate, heterogeneous conditions. Among various polarizable force fields, our lab has been developing the Drude polarizable force field (FF). Although the Drude polarizable FF has undergone thorough parametrization for biomolecules and ion-water interactions, our research found limitations in its capability to accurately depict ion-biomolecular interactions. In our recent publication, we established a protocol for crafting atom-pair specific Lennard-Jones parameters (referred to as NBFIX in CHARMM) and through-space Thole dipole screening (NBTHOLE) using data from readily accessible quantum mechanical (QM) calculations. This approach is aimed at optimizing the Drude polarizable force field to reproduce both gas phase QM data and condensed-phase experimental thermodynamic benchmarks. Our investigations have verified that this protocol effectively reproduces interactions between monovalent ions and functional groups. However, further development is needed to assess its applicability to divalent ions. A challenge in divalent ion - functional group interactions is the necessity of including multi-body interactions, including the treatment of explicit water molecules in the QM calculations, owing to the heightened electrostatic strength exerted by the ions on the surrounding environment. In the present work, we develop a protocol to balance the interactions of divalent ion (specifically Mg⁺, and Ca⁺) with functional group present in biological molecules based on QM data. The validation of this protocol is performed through condensed phase osmotic pressure calculation on varying ion concentrations (0-3 M). We find that the NBTHOLE term, which is used to optimize ion-model compound interactions through adjusting specific atomic dipole-dipole interactions, plays an important role in divalent ion parametrization. These efforts have led to improved Drude parameters for the divalent ions offering enhanced understanding of molecular interactions within MD simulations, providing valuable insights to researchers across various scientific disciplines.