Missing pieces in structure puzzles – How Hyperpolarized NMR can complement structural biology and biochemistry

Structure determination lies at the heart of many biochemical research programs. However, the ‘giants,’ X-ray diffraction, electron microscopy, molecular dynamics simulations, and nuclear magnetic resonance (NMR), among others, leave quite a few dark spots on the structural pictures drawn of proteins, nucleic acids, membranes, and other biomacromolecules. For example, structural models under physiological conditions or of short-lived intermediates often remain out of reach of the established experimental methods. The present account frames the possibility of including hyperpolarized, i.e., dramatically signal-enhanced NMR into existing workflows to fill these spots with detailed depictions. We highlight that integrating methods based on dissolution dynamic nuclear polarization can provide valuable complementary information about formerly inaccessible conformational spaces for many systems. A particular focus will be on hyperpolarized buffers to facilitate NMR structure determination of challenging systems.