Protein NMR: Boundless opportunities.

Over the past approximately three decades, isotope-directed NMR spectroscopy has become a powerful method for determining 3D structures of biological macromolecules and their complexes in solution. From a structural perspective NMR provides an invaluable tool for studying systems that are not amenable to crystallization, including intrinsically disordered proteins and weak complexes. In contrast to both X-ray crystallography and cryo-electron microscopy which afford a largely static view of the systems under consideration, the great power of NMR lies in its ability to quantitatively probe exchange dynamics between interconverting states, and to reveal and characterize at atomic resolution the existence of transient states that may be populated at levels as low as 1%. Such "excited" states play a key role in macromolecular recognition, allostery, signal transduction and macromolecular assembly, including the initial events involved in aggregation and amyloid formation. Optimal application of NMR to such systems of fundamental biological interest requires a sound footing of the physical underpinnings of today's and tomorrow's sophisticated NMR experiments.