NMR studies of mobility within protein structure

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Abstract
NMR studies of dynamics within structure have revealed that a quite new approach to protein structure and its relation to function is necessary. This approach requires the consideration in detail of the following: 1. Local movements of groups and small segments to allow fast recognition and fitting. The motion concerns on/off rates as well as binding. The observations affect surface/surface recognition, e.g. of antigen/antibody as well as of substrate and protein. 2. Somewhat larger interdomain or N- and C-terminal segments which allow rearrangement. Cases in point are the movement of segments in blood-clotting proteins or in histones. 3. Relative motion of helices in hinges. These actions are likely in such enzymes as kinases and P-450 cytochromes. 4. Relative motion of helices within domains (relative to other helices or sheets) in mechanical devices (triggers) e.g. in calmodulin. 5. General motion in random proteins. Examples extend from rubber-like proteins (entropy sensors), some glycoproteins, to proteins carrying peptide hormones to be generated only after hydrolysis. 6. Order----disorder transitions locally as in osteocalcin and metallothionine. 7. Swinging arm motions associated with special sequences such as (Ala-Pro)n. 8. Of great interest is the power of NMR to look at proteins which are relatively large, up to 50 kDa proteins, and to isolate certain zones of interest. This needs careful temperature dependent studies and analysis of separated domains [72] as well as the use of a great variety of pulse sequences [15] and of nuclei other than protons. 9. In this article I have illustrated the different possibilities using work in my own group. This is done to lessen the burden of extensive review. I fully realise that the range of examples is now large. I would stress though that the production of the necessary technology was the endeavour of several of us within the Oxford Enzyme Group from 1970 to 1985, i.e. from 270-600 MHz Fourier-transform NMR spectroscopy. 10. While all of these features have been demonstrated by NMR methods there are parallel developments both using X-ray diffraction methods and theoretical approaches. All these procedures are changing the view of protein structure to one which incorporates dynamics all the way from conventional vibronic/rotational coupling to the disordered motions characteristic of random polymers. It is the understanding of dynamics that leads to an appreciation of function.