Computational insights into the interaction tendencies of fluoride-containing formulations with enamel-associated proteins

Fluoride-containing formulations are widely used in preventive dentistry; however, whether clinically used formulations exhibit distinct protein-level interaction tendencies that could be relevant to enamel biology remains insufficiently explored. In this study, we comparatively assessed four fluoride-containing formulations (sodium fluoride, amine fluoride/olaflur, sodium monofluorophosphate, and sodium difluorophosphate) against enamel-associated enzymes and matrix proteins using an in silico workflow. Molecular docking (AutoDock Vina) was performed against carbonic anhydrase II, tissue-nonspecific alkaline phosphatase, and matrix metalloproteinase-20, along with AlphaFold models of key enamel matrix proteins for hypothesis generation. Across targets, olaflur showed the most favorable docking scores and recurrent stabilizing contacts. Based on the docking rank and biological relevance, the olaflur– matrix metalloproteinase-20 complex was subjected to a 100-ns molecular dynamics simulation, demonstrating stable backbone deviation, limited residue-level fluctuations near the binding region, persistent hydrogen bonding, and favorable end-state binding free energy by Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). Collectively, these exploratory in silico results generate hypotheses suggesting that organic amine fluorides may display distinct molecular-level interaction tendencies with enamel-associated proteins, providing a basis for future experimental studies to examine their potential biological relevance.