Deuterium labeling greatly improves spectral quality and simplicity. (a) 1H‐1H NOESY spectrum of the full‐protiated (H, unlabeled) 155 nucleotides HIV‐1 core encapsidation signal (Keane et al., 2015) is characterized by severe signal overlap and broad line widths. (b) Selective deuteration of the sample results in spectra of significantly higher quality. There is minimal signal overlap and resonances are now effectively identifiable by the respective labeling scheme. Four different labeling schemes are shown: AH (adenosines protiated, cytosines, guanosines, and uracils deuterated), CH (cytosines protiated, adenosines, guanosines, and uracils deuterated), GH (guanosines protiated, adenosines, cytosines, and uracils deuterated), U6R (uracils protiated on the ribose and at C5, adenosines, cytosines, and guanosines deuterated)