Revisiting fluorine relaxation: a perspective on fluorine NMR in structural and dynamic studies of biomolecules

NMR is widely employed to investigate the structure and dynamics of biomolecules such as proteins and nucleic acids, owing to its unique ability to resolve signals from individual residue sites and thereby provide site-specific information. Among NMR spin probes, fluorine-19 (¹⁹F) has been extensively applied across diverse systems because of its favorable properties, including spin 1/2, 100 % natural abundance, low background signals, and high sensitivity to small variations in chemical environments. While advances in labeling strategies have expanded the applications of ¹⁹F, relatively less attention has been paid to its intrinsic relaxation properties; namely, how the longitudinal and transverse relaxation rates of ¹⁹F are defined and what types of magnetic interactions govern these relaxation processes. A major difficulty lies in the fact that ¹⁹F relaxation is affected by both intra- and inter-residual ¹H-¹⁹F dipole-dipole interactions as well as by its intrinsically large chemical shift anisotropy, complicating the quantitative interpretation of relaxation behavior. In this perspective, we revisit the theoretical background of ¹⁹F relaxation measurements, with particular focus on ¹H-¹⁹F interactions, aiming to provide guidelines for interpreting ¹⁹F NMR relaxation data and for developing novel experimental strategies.