NUCLEAR MA G NETIC RES O NA NCE F OURIER TRANSFOR M SPECTROSCOPY Nobel Lect ure, Dece mber 9, 1992 b y R IC H AR D R. E R N S T Laboratoriu m für Physikalische Che mie, Eidgenössische Technische Hoch- sch ule, E T H- Zentr u m 8092 Z urich, S witzerlan d T he worl d of t he n uclear s pi ns is a tr ue para dise for t heoretical a n d e x p eri m e nt al p h ysi cists. It s u p pli es, f or e x a m pl e, m ost si m pl e test s yst e ms for de monstrating the basic concepts of quantu m mechanics and quantu m statistics, an d n u mero us textbook-like exa m ples have e merge d. On the ot her ha n d, t he ease of ha n dli n g n uclear s pi n s yste ms pre desti nates t he m for testi ng no vel ex peri me ntal co nce pts. I n dee d, t he u ni versal proce d ures of coherent spectroscopy have been developed predo minantly within nucle- ar magnetic resonance ( N M R) and have found widespread application in a v ari et y of ot h er fi el ds. Se veral key ex peri me nts of mag netic reso na nce ha ve alrea dy bee n ho n- ore d b y p h ysics No bel prizes, starti ng wit h t he fa mo us molec ular bea m experi ments by Isi dor I. Rabi (1-3) ackno wle dge d in 1944, follo we d by the classical N M R experi ments by E d war d M. Purcell (4) an d Felix Bloch (5,6), h o n or e d wit h t h e 1 9 5 2 pri z e, a n d t h e o pti c al d et e cti o n s c h e m es b y Alfr e d K astl er ( 7), l e a di n g t o a pri z e i n 1 9 6 6. S o m e f urt h er p h ysi cs N o b el pri z e wi n ners have bee n associate d i n vario us ways wit h mag netic reso na nce: Jo h n H. Va n Vleck develo pe d t he t heory of dia- a n d para mag netis m a n d i ntro- d uce d the mo ment metho d into N M R, Nicolaas Bloe mbergen ha d a major i mpact on early relaxation theory and measure ments; Karl Alex Müller has contrib ute d significantly to electron para magnetic resonance; Nor man F. R a m s e y is r e s p o n si bl e f or t h e b asi c t h e or y of c h e mi c al s hifts a n d J co u pli ngs; a n d Ha ns G. De h melt has develo pe d p ure n uclear q ua dr u pole reso na nce. B ut not o nly for p hysicists is n uclear mag netic reso na nce of great fasci na- tio n. More a n d more c he mists, biologists, a n d me dical doctors discover N M R, not so m uc h for its co nce pt ual bea uty b ut for its extraor di nary usef ul ness. I n t his co ntext, a great n u mber of ma g netic reso na nce tools h a v e b e e n i n v e nt e d t o e n h a n c e t h e p o w er of N M R i n vi e w of a v ari et y of a p plicatio ns (8-15). T his Nobel lect ure provi des a gli m pse be hi n d t he scene of an N M R tool maker’s workshop. N uclear s pi n syste ms possess u ni q ue pro perties t hat pre desti nate t he m for molec ular st u dies: Ric h ar d R. Er nst 1 3 (i) The n uclear sensors provi de d by nat ure are extre mely well localize d, with a dia meter of a fe w fe mto meters, an d can re port on local affairs i n t h eir i m m e di at e vi ci nit y. It is t h us p ossi bl e t o e x pl or e m ol e c ul es a n d matter i n great detail. (ii) T he i nteractio n e ner g y of t he se nsors wit h t he e n viro n me nt is ex- tr e m el y s m all, wit h l ess t h a n 0. 2 J / m ol, c orr es p o n di n g t o t h e t h er m al e nergy at 30 m K, a n d t he mo nitori ng of molec ular pro perties is virt ually pert urbatio n-free. Nevert heless, t he i nteractio n is hig hly se n- sitive to t he local e nviro n me nt. (iii) Geo metrical i nfor matio n ca n be obtai ne d fro m n uclear pair i nterac- tio ns. Mag netic di polar i nteractio ns provi de dista nce i nfor matio n, w hil e s c al ar J- c o u pli n g i nt er a cti o ns all o w o n e t o d et er mi n e di h e dr al b o n d a n gl es. O n first si g ht, it m a y b e ast o nis hi n g t h at it is p ossi bl e t o a c c ur at el y d et er- mine intern uclear distances by ra dio freq uencies with wavelengths 1 m, t h at s e e mi n gl y vi ol at e t h e q u a nt u m m e c h a ni c al u n c ert ai nt y r el a- ti o n, wit h t h e li n e ar m o m e nt u m p = 2 π h / λ , as it a p pli es t o scattering ex peri ments or to a microsco pe. It is i m portant that in magnetic r es o n a n c e t h e g e o m etri c i nf or m ati o n is e n c o d e d i n t h e s pi n H a milt o ni a n, w h er e are t he n uclear coor di nates. A n acc urate geo metric measure ment, therefore, boils do wn to an accurate energy mea- s ure ment that can be ma de as precise as desire d, provi de d that the observa- ti o n ti m e t is e xt e n d e d a c c or di n g t o A n u p p er li mit of t is i n practice give n by t he fi nite lifeti me of t he e nergy eige nstates d ue to relax- ation processes. Thus, the accuracy of N M R measure ments is not restricte d by t he wavele ngt h b ut rat her by relaxatio n-li mite d lifeti mes. The infor mation content of a nuclear spin Ha miltonian an d the associat- e d relaxation s u pero perator of a large molec ule, e.g. a protein, is i m mense. It is p ossi ble t o deter mi ne t he c he mical s hift fre q ue ncies of h u n dre ds of s pins in a molec ule to an acc uracy of 16-18 bits. Intern uclear distances for thousan ds of proton pairs can be measure d to about 0.1 A. Several hun dre d dihe dral angles in a molec ule can be deter mine d with an uncertainty of less t h a n 1 0°. T he wea k ness of t he n uclear s pi n i nteractio ns, so far descri be d as a n a d va ntage, lea ds o n t he ot her ha n d to se vere detectio n proble ms. Large n u mbers of s pins are req uire d to discri minate the weak signals fro m noise. Un der o pti m u m con ditions with mo dern high fiel d N M R s pectro meters, 1 0 1 4 - 1 0 1 5 s pi ns of o n e ki n d ar e n e e d e d t o d et e ct a si g n al wit hi n a p erf or m- a n c e ti m e of o n e h o ur.