Chemical shift-based methods in NMR structure determination

Abstract

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 side-chain 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.

Monitoring the Site-Specific Solid-State NMR Data in Oligopeptides

“…This type of monitoring is presented here for samarosporin I (a naturally occurring peptaibol comprised of 15 amino acids [16]) on the basis of benchmarking calculations for a set of six triglycines, and for N-Ac-Aib-OH, N-Ac-Leu-OH and Ala-Pro-Gly dihydrate, after their assessment performed for melanostatin (Pro-Leu-Gly-NH 2 hemihydrate [17]). The results directly capture an influence of secondary structural elements upon the NMR parameters (see reference [18] for the most recent review of this topic) and could be important in NMR crystallography [19][20][21][22][23] of oligopeptides and in an interpretation of spectra of their oriented samples [24].…”

Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds

“…2e) and XAA_GVDQ (Fig. 4d)) (Nerli et al, 2018) . In (ii), we used a uniform upper distance bound of 10 Å for all 92 NOE restraints for XAA and for all 139 NOE restraints for XAA_GVDQ (Table S5).…”

Computational design of closely related proteins that adopt two well-defined but structurally divergent folds

“…2E] and XAA_GVDQ [ Fig. 4D]) (49). In the second set of calculations, we used a uniform upper distance bound of 10 Å for all 92 NOE restraints for XAA and for all 139 NOE restraints for XAA_GVDQ (SI Appendix, Table S5).…”