Chemists have used chemical shifts for more than 50 years as highly reproducible, easily measured parameters to map out the covalent structure of small organic molecules.
Indeed, the sensitivity of NMR chemical shifts to the type and character of neighbouring atoms, combined with their reasonably predictable tendencies has made them invaluable for both deciphering and describing the structure of thousands of newly synthesized or newly isolated compounds[1] [2] [3][4] The same sensitivity to a variety of important protein structural features has made protein chemical shifts equally valuable to protein chemists and biomolecular NMR spectroscopists.
[4] In particular, protein chemical shifts are sensitive not only to substituent or covalent atom effects (such as electronegativity, redox states or ring currents) but they are also sensitive to backbone torsion angles (i.e. secondary structure), hydrogen bonding, local atomic motions and solvent accessibility.
These improvements have also been helped along through significant computational advancements [5] [6] [7] [8] and the rapid expansion of biomolecular chemical shift databases [9] .
[1][4] By early 2000, several research groups realized that protein chemical shifts could be more efficiently and accurately calculated by combining different methods together as shown in Figure 1.