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_Thls Week’s Citation CIassic~FEBRUARY 5~99O Eigen M. Proton transfer, acid-base catalysis, and enzymatic hydrolysis. Part 1: elementary processes. Angew. Chem. 75:489, 1963: Angew. Chem. mt. Ed. 3:1-19. 1964; and Selforganization of matter and the evolution of biological macromolecules. Nazurwissenschaften 58:465-523, 1971. [Max-Planck-lnst. 113r Biopbysikalische Chemie. Karl-Friedrich-Bonhoeffer-Inst.. GottingenNikolausberg, Federal Republic of Germany] 1963: The development of relaxation techniques made possible a quantitative study of fast elementary reactions and a dissection of complex reaction mechanisms, which could be explained in terms of elementary steps. Application to biological reactions led to the conclusion that enzymes are optimal catalysts. [The SCI® indicates that this paper has been cited in the 1963 form in over 285 publications and in the international edition (1964) in over 965 publications.] Schwarz, Georg Czerlinski, Hartmut Diebler, Walter Kruse, Günter Maass, and Georg Ilgenfritz—among others—contributed much to this early technologically oriented phase of work. Waves of visitors, students, postdocs, and professors (on sabbatical leave), who came from all over the world, swept through our laboratory. I remember that it was always crowded. We had a high turnover of both staff and machines because many coworkers took home either a secretary or a T-jump device 1971: Biological self-organization is based on when they left. The first wave of visitors connatural selection. A prerequisite of natural se- sisted mostly of inorganic chemists. They were lection is self- or complementary-reproduction. followed by the organic chemists who evenSuch a process generates information, which mixed with the biochemists. Today the is the physical basis of life. [The Sd® indicates tually center of gravity has shifted to what we call that the Naturwissenschaften paper has been cited in over 490 publications, making it the molecular biology (including mathematics, physics, chemistry, microbiology, genetics, and most-cited paper for this journal.] even electrotechnics). After it had become possible, using the methods of relaxation spectrometry, todissect complex reactions into theirelementary steps, p and thereby measure the rates of very fast processes such as the transfer of protons through hydrogen bonds, it was merely a matter of a few years before these new tools were applied Enzymes Are Optimal Catalysts to biochemical processes and enzyme mechanisms2 were elucidated in every molecular Manfred Eigen detail. It was not at all surprising to find that Karl-Friedrich-Bonhoeffer-Institut these molecular gadgets, whose biological oriMax-Planck-Institut für gin is a notorious problem, obey the laws of Biophysikalische Chemie physics and chemistry. Wherever a violation D-3400 Göttingen-Nikolausberg of these laws seemed to occur, detailed analy. Federal Republic of Germany sis uncovered nature’s tricks. An example is pertinent: The maximum speed of a bimolecular reaction is limited by the encounter rate based on the diffusional motion of both reacOctober 18, 1989 tion partners. However, for the binding ofthe lac-repressor to its DNA operator site, a value exceeding the maximum rate constant for a The two Citation Classics—both written diffusion controlled process by one to two orders of magnitude was obtained (depending within an interval of seven years—seem, at first sight, entirely unrelated. This impression, how- on reaction conditions such as ionic strength, ever, is superficial. There is, indeed, a strong etc.). It turned out that neither theory was internal tie that becomes obvious if we analyse wrong nor was there any demon at work. The the objective and subjective motives that led repressor is able to bind at any DNA site via to the writing of these articles. electrostatic interaction after which it is During the 1950s most of our work con- guided through one-dimensional diffusion 3 along the helix-axis into the operator site. cerned the development of relaxation tech1 Other studies even revealed “intelligent” reacniques for studying fast reactions in solution. Leo DeMaeyer, Joseph Schoen, Gerhard tion behaviour of enzymes. With the new tech16 ©1990 by SI® — C ~/ET / ~~~e:’ CURRENT CONTENTS ® niques, we were able for the first time to break tures, but on the molecular level only nucleic down4an allosteric mechanism into its single acids inherit this ability. (My late friend Sol steps. Jacques Monod was delighted to find Spiegelman used to say: Man is only a trick his cooperative model of. allosterism fully of nucleic acids to reproduce even under confirmed.’ strange conditions, for instance, on the moon). Our conclusion that “enzymes are optimal However, the theory was not just an adoption catalysts” is to be understood in this sense: of Darwin’s tenets and their application to they are best adapted, given a number of molecules. What finally resulted was a picture sometimes counteracting constraints. Optimal ofa much more subtle nature: Selection at the efficiency does not plainly mean maximum molecular level appears to be a “phase tranphysical speed; it may involve an optimal com- sition” in information space. promise between specificity, speed, stability, Information melts away whenever an error and other chemical constraints, and in some threshold—well defined by the theory—is excases it may involve “intelligent” control of ceeded. Notice that it is not matter that melts rate and specificity. away. Rather it is information that represents If all this is true, we are forced to ask: Who functional meaning. Thisproperty is as immaconstructed those optimal gadgets? The biol- terial as Mozart’s music, which also has to be ogist will answer: natural selection! But what fixed on (material) scores. Information is a does this mean, if molecules rather than living property that transcends the material charent~*iesare involved? What is the target of se- .acter of chemistry and distinguishes a living lection? Molecular structures usually prevail organism from any chemical composite, no because they represent states ofminimum po- matter how complex. tential energy. Why should such a property co- Sequence space, fitness landscapes, quasiincide with optimal functional performance? species, and hypercycles are abstract concepts Is biological organization at the molecular that have been developed in order to underlevel at all a physical problem? Isn’t optimal stand complex reality rather than to describe efficiency of enzymes rather the result of or represent it.56 Meanwhile these concepts chance and therefore unique and not repro- have been tested experimentally and are the7 ducible? Or are there physical principles, sim- basis of a new evolutionary biotechnology. ilar to the extremum principles of thermody- At the same time, sequence space, error threshold, and quasi-species are concepts that namics, that guarantee optimal solutions? It was clear from the beginning that the so- are reflected most directly in the reality of viral t111 lution ofthe problem had tobe of a Darwinian life. type, although Darwin had never dealt with Peter Schuster, now at the University of molecules. It turned out that no equilibrium Vienna, was an early partisan in the develop5 theory of molecular organization could do the ment of all these ideas. He, and later john job and that one of the principle requirements McCaskill and others, contributed many origof selection and evolution is self-reproduction. inal thoughts towhat now appears to be a wellThe prerequisite is fulfilled by all living crea- established edifice.6 I. Eigen M. Kinetics of reaction control and information transfer in enzymes and nucleic acids. (Claesson S. ed.) Nobel Symposium 5. Stockholm. Sweden: Almqvist A WikseU. :967. p. 333-69. (Cited 80 times.) 2. . New looks and outlooks on physical enzymology. Quart. Rev. Biopltys. 1:3-33, 1968. (Cited 85 times.) 3. Richter P H & Eigen M. Diffusion controlled reaction rates in spheroidal geometry. Application to repressor-operator association and membrane bound enzymes. Biophys. Chum. 2:255-63. 1974. (Cited 140 times.) 4. Klrschner K. Eigen M, Bittman R & Voigt B. Th~ binding of sicotin, amide-adenine dioucleotide to yeast d-glyceraldehyde-3-phosphate dehydrogenase: temperature jump relaxation studies on the mechanism of an aflosteric enzyme. Proc. Nat. Acad. Sci. USA 56:1661-7, 1966. (Cited 185 times.) 5. Elgen M & Schuster P. The hypercycle. A principle oi natural self-organization. Heidelberg, FRG: Springer-Verlag, 1979. 92 p. (Cited 160 times.) 6. Elgen M, McCaskill J & Schuster P. Molecular quasi-species. I. Phys. Chem. 92:6881-91, 1988. 7. Eigen M & Gardiner W. Evolutionary molecular engineering based on RNA replication. Pure App). Chem. 56:967-78, 1984. 8. Biebricher C K & Elgen M. Kinetics of R.NA replication by QB-replicase. (Domingo E. Holland J I & Ahlquist P. eds.) RNA generics. Boca Raton. FL: CRC Press, 1988. Vol 1. p. 1-21. 9. Elgen M & Biebricher C K. Sequence space and quasi-species distribution. (Domingo E, Holland ii & Ahlquist F, mis.) RNA generics. Boca Raton, FL: CRC Press, 1988. Vol. lfl. p. 211-45. 10. Meyerhans A, Cheynier R, Albert J, Seth M, Kwok 5, Sninsky J, Morfeldo.Manson L, Asjo B & Wain-Hobson S. Temporal fluctuations in 1{IV quasispecies in vivo are not reflecled by sequential HIV isolations. Ccli 58:901-10, 1989. II. Mateu M G, Martinez M A, Rocha E, Andren D, Parejo J, Giralt E, Sobrino F & Domingo K. Implications of a quasispecies gettome structure: effect of frequent, naturally occurring amino acid substitutions on the antigenicity of foot and mouth disease virus. Pltrc. Nal. Acad. Sri. USA 86:5883-7, 1989. CURRENT CONTENTS® ©1990 by (SI® ET&AS, V. 21, #6, Feb. 5, 1990 17