Chemical shift-based methods in NMR structure determination

Prog Nucl Magn Reson Spectrosc. 2018 Jun-Aug:106-107:1-25. doi: 10.1016/j.pnmrs.2018.03.002. Epub 2018 Mar 11.


Chemical shifts are highly sensitive probes harnessed by NMR spectroscopists and structural biologists as conformational parameters to characterize a range of biological molecules. Traditionally, assignment of chemical shifts has been a labor-intensive process requiring numerous samples and a suite of multidimensional experiments. Over the past two decades, the development of complementary computational approaches has bolstered the analysis, interpretation and utilization of chemical shifts for elucidation of high resolution protein and nucleic acid structures. Here, we review the development and application of chemical shift-based methods for structure determination with a focus on ab initio fragment assembly, comparative modeling, oligomeric systems, and automated assignment methods. Throughout our discussion, we point out practical uses, as well as advantages and caveats, of using chemical shifts in structure modeling. We additionally highlight (i) hybrid methods that employ chemical shifts with other types of NMR restraints (residual dipolar couplings, paramagnetic relaxation enhancements and pseudocontact shifts) that allow for improved accuracy and resolution of generated 3D structures, (ii) the utilization of chemical shifts to model the structures of sparsely populated excited states, and (iii) modeling of sidechain conformations. Finally, we briefly discuss the advantages of contemporary methods that employ sparse NMR data recorded using site-specific isotope labeling schemes for chemical shift-driven structure determination of larger molecules. With this review, we aim to emphasize the accessibility and versatility of chemical shifts for structure determination of challenging biological systems, and to point out emerging areas of development that lead us towards the next generation of tools.

Keywords: Automated methods; CS-Rosetta; Chemical shifts; Hybrid methods; NMR structure determination; Protein structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Humans
  • Magnetic Resonance Spectroscopy / methods*
  • Models, Molecular
  • Nucleic Acid Conformation
  • Nucleic Acids / chemistry
  • Protein Conformation
  • Proteins / chemistry


  • Nucleic Acids
  • Proteins