ChemBioChem 2003, 4, 135 ± 142 ¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1439-4227/03/04/2-3 $ 20.00+.50/0 135 Kurt W¸thrich, the ETH Z¸rich, and the Development of NMR Spectroscopy for the Investigation of Structure, Dynamics, and Folding of Proteins Harald Schwalbe* [a] KEYWORDS: history of science ¥ NMR spectroscopy ¥ Nobel prize ¥ protein folding ¥ protein structures General George Patton was the military leader of the American Third Army in World War II. Starting in 1944, the Third Army advanced through Brittany, round Paris, up the Marne and the Moselle, across the Rhine, and eventually into Czechoslovakia in April 1945. Patton was known for his short and sharp addresses to his troops. In one of those speeches, he welcomed the 761st Black Panther Tank battalion, the first battalion to admit black soldiers to the army. He ended his speech for the soldiers with the following sentences: ™Everyone has their eyes on you and [is] expecting great things from you. Most of all, your race is looking forward to your success. Don't let them down, and damn you, don't let me down! If you want me you can always find me in the lead tank.∫ [1] Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful techniques to study the structure, dynamics, and folding of proteins. This view has been recognized by the Nobel prizecommitteebyawardingonehalfofthe2002Nobelprizein Chemistry to Prof. Kurt W¸thrich, of the Eidgenˆssische Techni- sche Hochschule (ETH) Z¸rich, ™for his development of nuclear magnetic resonance spectroscopy for determining the three- dimensional structure of biological macromolecules in solution.∫ And indeed, when summarizing W¸thrich's scientific contri- butionstothisfield,onehastotellthestoryofthedevelopment ofNMRspectroscopyforthestudyofbiologicalmacromolecules in general and of proteins in particular (Table1). This develop- ment has been driven by a battalion of outstanding researchers, amongst which, like General Patton during the Allied invasion in 1944, W¸thrich could always be found in the lead tank. And similarly, W¸thrich's scientific orientation has been and contin- ues to be focused, ambitious, and straight. W¸thrich's first encounter with magnetic resonance was during his PhD research with Silvio Fallab in Basel, where he studied the mechanism of Cu 2 -catalyzed reactions [2] and VO 2 complexes [27] by using electron spin resonance spectroscopy. He joined RobertE. Connick as a postdoctoral fellow at Berkeley, California, where he published his first NMR spec- troscopy paper entitled ™Nuclear magnetic resonance relaxa- tion of oxygen-17 in aqueous solutions of vanadyl perchlo- rate and the rate of elimination of water molecules from the first coordination sphere∫. The paper deals with 17 O NMR spectroscopy of paramagnetic vanadylate perchlorate. [28] Interestingly, W¸thrich later studied the dynamics of hy- dration in proteins–old questions investigated under a new angle. From paramagnetic inorganic salts to paramagnetic proteins The first NMR spectrum of the protein ribonuclease was studied bySaundersetal. [29] in1957.W¸thrich'sfirstproteinNMRstudies, together with Bob Shulman, dealt with the paramagnetic protein cyanometmyoglobin and were published in 1968. [3] In 1970, the young Privatdozent W¸thrich published an article in Chimia on the ™study of the spatial structure of protein molecules by NMR spectroscopy∫. [4] This was seven years after Kendrew and Perutz had solved the first three-dimensional structures of the proteins myoglobin [30] and haemoglobin [31] by X-raycrystallography.ByshowingwhetherNMRinvestigationsof proteins in solution and X-ray studies of proteins in their crystalline form would yield similar spatial structures of proteins under the widely different experimental conditions, W¸thrich intended to provide an important cross-validation for both techniques. In addition, he continued, NMR spectroscopy could be applied to investigate the structural properties of proteins under conditions that do not yield crystals. What in hindsight turned out to be the topic of his life must have evoked some scepticism at the time of this initial publication. It took W¸thrich's courage and determination for over thirty years to prove that his claim to be able ™to solve the structure of a protein∫, put forward in his unique and charming [a] H. Schwalbe Institute for Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance Johann Wolfgang Goethe-University Frankfurt Marie-Curie-Strasse 11, 60439 Frankfurt/M (Germany) Fax: ( 49) 69-798-29515 E-mail : schwalbe@nmr.uni-frankfurt.de