Over the last decades, NMR spectroscopy has grown into an indispensable tool for chemical analysis, structure determination, and the study of dynamics in organic, inorganic, and biological systems. It is commonly used for a wide range of applications from the characterization of synthetic products to the study of molecular structures of systems such as catalysts, polymers, and proteins. Although most NMR experiments are performed on liquid-state samples, solid-state NMR is rapidly emerging as a powerful method for the study of solid samples and materials. This Review outlines some of the developments of solid-state NMR spectroscopy, including techniques such as cross-polarization, magic-angle spinning, multiple-pulse sequences, homo- and heteronuclear decoupling and recoupling techniques, multiple-quantum spectroscopy, and dynamic angle spinning, as well as their applications to structure determination. Modern solid-state NMR spectroscopic techniques not only produce spectra with a resolution close to that of liquid-state spectra, but also capitalize on anisotropic interactions, which are often unavailable for liquid samples. With this background, the future of solid-state NMR spectroscopy in chemistry appears to be promising, indeed.

Solid-state NMR spectroscopic methods in chemistry.

An overview is given of the recent development and use of density functional methods in nuclear magnetic resonance (NMR) chemical-shift calculations. The available density functional theory (DFT) methods are discussed, and examples for their validation and application are given. Relativistic effects are also considered, with an emphasis on spin–orbit coupling. The systems discussed range from transition-metal complexes and clusters via biological systems and fullerenes to weakly bound van der Waals molecules. DFT results not published previously comprise spin–orbit effects on 31P chemical shifts in phosphorus halides, the orientation of the 31P-shift tensor in Ru4(PPh)(CO)13, δ(95Mo) data, 13C and endohedral chemical shifts for fullerenes and for C60H36, as well as the shielding surface of the Ne2 molecule. © 1999 John Wiley & Sons, Inc. J Comput Chem 20: 91–105, 1999

The DFT route to NMR chemical shifts

G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of 13C,15N-labeled NT(8–13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a β-strand conformation. Our results provide a viable structural template for further pharmacological investigations.

The conformation of neurotensin bound to its G protein-coupled receptor

NMR studies of Brownian tumbling and internal motions in proteins

A robust technique for two-dimensional separation of undistorted chemical-shift anisotropy powder patterns in magic-angle-spinning NMR.

A simple method for the determination of backbone dihedral angles in peptides and proteins is presented. The chemical-shift anisotropies (CSA) of the central alanine α-carbon in powdered crystalline tripeptides, whose structures have been determined previously by X-ray crystallography, were measured by cross-polarization magic-angle-spinning nuclear magnetic resonance. The experimental CSA values were correlated with ab initio chemical-shielding calculations over Ramanchandran φ/ψ space on an N-formyl-l-alanine amide fragment. Using this correlation, φ/ψ probability surfaces for one of the tripeptides were calculated based only on the α-carbon CSA, allowing a prediction of backbone angles. Dihedral angles predicted by these calculations fall within ±12° of the values determined by crystallography. This approach should be useful in the determination of solid-state protein structure.

M. Tomaselli

Papers

Determination of Dihedral Angles in Peptides through Experimental and Theoretical Studies of α-Carbon Chemical Shielding Tensors