Recent developments in NMR spectroscopy have pushed the boundaries of structural biology and enabled the investigation of biological molecules, large and small, in complex and native environments. However, the application of NMR in the cellular setting is still challenging due to the inherently low sensitivity of magnetic resonance techniques and the difficulty of selectively labeling only the component of interest in the crowded cellular environment. To address these challenges, my group has developed a targeted dynamic nuclear polarization (targeted DNP) approach that allows us to select a protein of interest in a complex mixture and to uniquely enhance its NMR signals over background. In particular, we have developed a targetable DNP polarization agent functionalized with a tetrazine moiety that can react selectively and efficiently with unnatural amino acids containing a strained cycloalkene. The unnatural amino acid, in turn, can be installed on the protein of interest by genetic means. The bio-orthogonal chemical reaction between tetrazines and strained cycloalkenes directs the attachment of the polarization agent to the target protein, thus enabling selective DNP. Unlike other targeted DNP strategies, this approach is compatible with any protein of interest and applicable to both bacterial and mammalian cells. Here, I will present several applications of this technique to proteins in native environments, and I will discuss the mechanisms of DNP polarization transfer in these complex biological settings.

Mechanisms and biological applications of targeted dynamic nuclear polarization

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