Molecular dynamics (MD) simulation is a widely used tool to study molecular behavior with atomic precision. In MD simulations an accurate force field is required for convincing and rigorous results. Traditional additive force fields, which average the effect of atomic polarizability, have been challenged in capturing the electronic response to heterogeneous environments. As a result, additive fore fields usually yield bad reproducibility of experimentally observed thermodynamic properties in systems containing high ionic concentrations with heterogeneous environments. Such heterogeneity is ubiquitous in biological systems (i.e., ion channels, ion bridging) and other industrial applications. Better describing the heterogeneous environmental response of polarizable atoms (i.e., ions around different protein functional groups) can improve the atomistic understanding of molecules obtained from MD simulations. In the present work we refine the interactions between monoatomic ions (Na+, K+, and Rb+ ) and typical functional groups present in biomolecules using a polarizable force field based on the classical Dude oscillator model. Previously, ion parameters were optimized to reproduce the hydration free energies and coordination geometries with water in the Drude-2013 force field. In the present work, instead of reparameterizing existing ion, biomolecule, and water parameters, we use the pair-specific LJ term (called NBFIX in CHARMM) and through-space Thole dipole screening term (NBTHOLE) to fit a combination of quantum mechanical (QM) and experimental target data. NBFIX overcomes the limitations due to LJ interactions being calculated using predefined combination rules. We target the gas-phase QM interaction energies as well as condensed phase osmotic pressure under varying ion concentrations. In addition to single ion-model compound interaction energies, multiple ion and model compound interactions are targeted for parameter optimization, with the latter shown to be more representative of interactions occurring on an aqueous environment. This approach is anticipated to lead to an important refinement of the Drude polarizable FF parameters for modeling ion-biomolecular interactions.

Balancing monoatomic ion-biomolecular interactions in the polarizable Drude force field

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