Abstract
Solution NMR spectroscopy is a particularly powerful technique for characterizing the functional dynamics of biomolecules, which is typically achieved through the quantitative characterization of chemical exchange processes via the measurement of spin relaxation rates. In addition to the conventional nuclei such as 15N and 13C, which are abundant in biomolecules, fluorine-19 (19F) has recently garnered attention and is being widely used as a site-specific spin probe. While 19F offers the advantages of high sensitivity and low background, it can be susceptible to artifacts in quantitative relaxation analyses due to a multitude of dipolar and scalar coupling interactions with nearby 1H spins. In this study, we focused on the ribose 2′-19F spin probe in nucleic acids and investigated the effects of 1H-19F spin interactions on the quantitative characterization of slow exchange processes on the millisecond time scale. We demonstrated that the 1H-19F dipolar coupling can significantly affect the interpretation of 19F chemical exchange saturation transfer (CEST) experiments when 1H decoupling is applied, while the 1H-19F interactions have a lesser impact on Carr-Purcell-Meiboom-Gill relaxation dispersion applications. We also proposed a modified CEST scheme to alleviate these artifacts along with experimental verifications on self-complementary RNA systems. The theoretical framework presented in this study can be widely applied to various 19F spin systems where 1H-19F interactions are operative, further expanding the utility of 19F relaxation-based NMR experiments.
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Code availability
The Python scripts and the Bruker-format pulse programs used in this study are available on https://github.com/YukiToyama/19F_CEST.
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Acknowledgements
The authors are grateful to Prof. Lewis E. Kay (University of Toronto) for critical reading of the manuscript and many useful suggestions. This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP21ae0121028 for I.S.
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Funding was provided by Japan Agency for Medical Research and Development (Grant No. JP21ae0121028).
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YT concevied the project, prepared NMR samples, performed NMR experiments, carried out simulations, and analyzed the data. YT and IS wrote the manuscirpt.
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Toyama, Y., Shimada, I. Quantitative analysis of the slow exchange process by 19F NMR in the presence of scalar and dipolar couplings: applications to the ribose 2′-19F probe in nucleic acids. J Biomol NMR (2024). https://doi.org/10.1007/s10858-024-00446-7
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DOI: https://doi.org/10.1007/s10858-024-00446-7