Chemical shifts are receiving renewed attention in structural biology owing to the recent introduction of novel methodologies that enable their use in protein structure determination.[1–10] As these approaches have so far been mostly concerned with backbone atoms, it would be highly desirable to further generalize them to also include side-chain atoms.[11–14] A major motivation for this objective is that side chains play crucial roles in determining the conformational properties of protein surfaces and interior cavities, which in most cases define the specificity of biomolecular interactions. In particular, aromatic side chains are capable of forming interactions with a variety of chemical groups through hydrophobic, π–π stacking, π–anion and π–cation interactions, and often comprise the hot spots of protein–protein [15] and protein–ligand [16] complex formation, and protein folding.[17] Furthermore, aromatic side chains, as sources of ring current effects, substantially influence the chemical shifts of other nuclei, including the highly exploited backbone nuclei. However, although ring-current terms are frequently included in chemical shift predictions of backbone nuclei, aromatic chemical shifts are not normally used to define the geometry of the aromatic rings themselves. Recent advances in specific labeling technologies for aromatic side chains [18, 19] will soon increase the number of assigned aromatic chemical shifts, thus adding new prospects to the established methodology of aromatic chemical shift measurements.[20] The incorporation of chemical shifts of aromatic side chains in structure-determination algorithms, in addition to the backbone atoms, would make it possible to extend the use of chemical shifts in structural studies. To achieve this goal, a chemical shift prediction method for side-chain nuclei that is based solely on the configurations of proximal atoms needs to be developed.[21]

This type of predictions, which is at variance with other currently available chemical shift predictors that provide chemical shift evaluations for side-chain nuclei,[22–25] are readily differentiable with respect to the atomic coordinates, and thus enable the calculation of biasing forces for the integration of the equations of motion within a molecular dynamics scheme.[8] Prediction of aromatic side-chain chemical shifts by differentiable functions opens new opportunities to monitor a range of important processes, and will increase the scope of chemical shift usage in determining the structures of biomolecular complexes and complex biomolecular sys-