Balancing Group\n1 Monoatomic Ion–Polar Compound\nInteractions in the Polarizable Drude Force Field: Application in\nProtein and Nucleic Acid Systems

An accurate force field (FF) is the foundation of reliable\nresults\nfrom molecular dynamics (MD) simulations. In our recently published\nwork, we developed a protocol to generate atom pair-specific Lennard-Jones\n(known as NBFIX in CHARMM) and through-space Thole dipole screening\n(NBTHOLE) parameters in the context of the Drude polarizable FF based\non readily accessible quantum mechanical (QM) data to fit condensed\nphase experimental thermodynamic benchmarks, including the osmotic\npressure, diffusion coefficient, ionic conductivity, and solvation\nfree energy, when available. In the present work, the developed protocol\nis applied to generate NBFIX and NBTHOLE parameters for interactions\nbetween monatomic ions (specifically Li<sup>+</sup>, Na<sup>+</sup>, K<sup>+</sup>, Rb<sup>+</sup>, Cs<sup>+</sup>, and Cl<sup>–</sup>) and common functional groups found in proteins and nucleic acids.\nThe parameters generated for each ion–functional group pair\nwere then applied to the corresponding functional groups within proteins\nor nucleic acids followed by MD simulations to analyze the distribution\nof ions around these biomolecules. The modified FF successfully addresses\nthe issue of overbinding observed in a previous iteration of the Drude\nFF. Quantitatively, the model accurately reproduces the effective\ncharge of proteins and demonstrates a level of charge neutralization\nfor a double-helix B-DNA in good agreement with the counterion condensation\ntheory. Additionally, simulations involving ion competition correlate\nwell with experimental results, following the trend Li<sup>+</sup> > Na<sup>+</sup> ≈ K<sup>+</sup> > Rb<sup>+</sup>.\nThese\nresults validate the refined model for group 1 ion–biomolecule\ninteractions that will facilitate the application of the polarizable\nDrude FF in systems in which group 1 ions play an important role.