(169at) Parametrization of Monatomic Ion-Biomolecular Interactions in the Polarizable Drude Force Field: Application in Protein and Nucleic Acid Systems

An accurate force field is the foundation of reliable results from Molecular dynamics (MD) simulations. The traditional additive force fields average the impact of atomic polarizability, which encounter difficulties in precisely capturing the electronic response across varied environments. As a result, these additive force fields often demonstrate limited reproducibility of thermodynamic properties observed in experimental conditions, especially in high ionic concentration systems and complex, heterogeneous conditions. This type of heterogeneity is prevalent in biological contexts, such as ion channels and nucleic acids, as well as in various industrial applications like Li⁺ ion batteries and ionic liquid systems. The advancement in polarizable force fields, which explicitly considers atomic polarizability, can tackle this issue. In our recently published work, we developed a protocol to generate atom-pair specific LJ (known as NBFIX in CHARMM) and through-space Thole dipole screening (NBTHOLE) based on readily accessible quantum mechanical (QM) data to fit condensed phase experimental thermodynamic benchmarks (osmotic pressure, diffusion coefficient, ionic conductivity, and solvation free energy) when available. It is worth noting that condensed-phase experimental properties are often unavailable for most functional groups and ion complexes. This protocol proves particularly beneficial in generating parameters for those lacking experimental data. In the present work, we further qualify the developed protocol to generate the NBFIX and NBTHOLE parameters in the application of the interactions between monoatomic ions (specifically Li⁺, Na⁺, K⁺, Rb⁺, and Cs⁺) and common functional groups found in proteins and nucleic acid systems. The parameters generated individually for each ion and functional group were allocated to their corresponding functional groups within proteins or nucleic acids. Subsequently, the distribution of ions around these functional groups in proteins and nucleic acids was examined. Our findings demonstrate that a modified force field successfully addresses the issue of over-binding observed in the previous iteration and accurately reproduces the effective charge of the protein. In addition, the simulation on nucleic acid in 100mM NaCl solution showed good agreement with the counterion condensation theory (CC) with DNA charge neutralized around 73 % (76% in CC theory) in the 1BNA system. This study aims to offer a more comprehensive and refined understanding of molecular interactions, extending beyond biological systems to encompass various fields across diverse scientific domains.