Thermodynamics of miRNA21 Adsorption on Silica Surfaces Probed with Parallel Tempering Metadynamics in the Well‐Tempered Ensemble

In this study, molecular dynamics (MD) simulations are used to investigate the adsorption of a 21‐nucleotide microRNA (miRNA21) to silica surfaces at three pHs, three salt concentrations, and with two salt species. Silica gel has been reported to be an effective biopreservation medium. MD simulations provided molecular‐level details of the adsorption processes that are expected to affect preservation efficacy. Parallel tempering metadynamics in the well‐tempered ensemble enhanced MD sampling and allowed the exploration of adsorbed, desorbed, compact, and extended miRNA21 conformations. Both CHARMM and AMBER force fields are used to explore conformational states. Simulation results indicate that higher salt concentrations correlate to increased binding strength, emphasizing the pivotal role of ion coordination in the adsorption process. Salt‐mediated miRNA–silica interactions are observed, indicating that cations can allow miRNA to approach the silica surface even when the surface is negatively charged. Simulations also revealed that acidic environments significantly weaken the adsorption between miRNA21 and silica surfaces due to fewer salt‐mediated interactions. These findings highlight the influence of environmental factors and salt‐mediated bridging interactions on RNA‐silica adsorption affinity. Simulations suggest that kinetics drive experimentally observed preservation activity. Reweighting of biased trajectories reveal key differences in RNA folding and ion coordination between force fields.