FIREX: Fast-Ion Replica EXchange Enables Rapid Sampling of Mg2+ Pairing with Nucleic Acids

Abstract We introduce Fast-Ion Replica EXchange (FIREX), a Hamiltonian Replica Exchange-based sampling strategy specifically designed to enhance the sampling of metastable divalent cation binding with phosphate groups, e.g., in nucleic acids. We parametrize the scheme and demonstrate its convergence and efficiency on a model DNA dodecamer with Mg2+ ions, using two force fields with very different ion-pairing properties to test its robustness. The highest replica is driven by a “fast-ion” Hamiltonian combining a reduced ion charge with a tuned pair-specific Lennard-Jones interaction between the ion and phosphate oxygen atoms, yielding rapid exchange as well as moderate binding affinity, amenable to efficient sampling. By enabling the robust quantification of divalent ion interactions in simulations, FIREX could be instrumental in refining force fields to better capture ion–molecule interactions. The provided guidelines for the design of fast-ion models suitable for FIREX are general and could be extended to other force fields or types of biomolecular moieties, such as carboxylated protein side chains, phosphorylated proteins, or other interaction sites on nucleic acids. We further demonstrate how FIREX can be efficiently combined with the REST2 method to achieve simultaneous sampling of ion binding and biomolecular conformations with the Amber-OL15-ECC force field, while convergence remains challenging with the original Amber-OL15. This shows that different HREX schemes, including REST2, can be merged into a combined, highly cost-effective HREX scheme and is a step toward robust, computationally efficient sampling of charged biomolecules in interaction with divalent ions.