Chemical shift-based methods in NMR structuredetermination

摘要

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 thestructures of sparsely populated excited states, and (iii) modeling ofside-chain conformations. Finally, we briefly discuss the advantages ofcontemporary methods that employ sparse NMR data recorded using site-specificisotope labeling schemes for chemical shift-driven structure determination oflarger molecules. With this review, we aim to emphasize the accessibility andversatility of chemical shifts for structure determination of challengingbiological systems, and to point out emerging areas of development that lead ustowards the next generation of tools.