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JEFFRIES WYMAN fune 2 I, ~ 90 I -November 4, ~ 995 BY ROBERT A. ALBERTY AND ENRICO DI CERA EFF~ES IAN WILL LONG be remembered for his contribu- | tions to our unclerstancling of the bincling of oxygen by iemogIobin en cl the linkage of this process with the binding of hydrogen ions en cl other species in the solution. In thinking about these complicates! interactions, the internal changes in the hemoglobin molecule, en cl its dissociation, {effries brought a deep understanding of thermodynamics and math- ematics. In his 50 years of research on these remarkable phenomena, which are also involvecl in enzyme catalysis, {effries's approach became increasingly sophisticated en cl general. He shower! how the concept of the bincling poten- tial unifiecl the treatment of all the equilibrium properties of these complicated systems, contributing greatly to our unclerstancling of cooperativity, linker! functions, allostery, en cl internal changes in proteins. He showocl how these concepts couIcl be extenclecl to treating systems in steacly states. During his life he was honored by membership in the National Academy of Sciences (1969), American Academy of Arts en cl Sciences, en cl the Italian Accaclemia clef Lincei, but the important thing was that he was sought out by bio- chemists around the worIcl for acivice en cl collaboration. {effries Wyman was born June ill, 1901, in West Newton, Massachusetts. His ancestors were New Englanclers en c! he 363

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364 B I O G RA P H I C A L EMOIRS was the thirc! in successive generations to bear that name. The first {effries Wyman ~ ~ 8 ~ 4-74) was a great comparative anatomist en cl the first director of the Peabody Museum of American Archeology en c! Ethnology at Harvard. He was one of the founcling members of the National Academy of Sciences in IS63. The second {effries Wyman was an officer in the Bell Telephone Company. When the third Jeffries entered Harvard College in 1919, he majored in philosophy. He graduated with highest honors in philosophy and with high honors in biology. During these years he developed an interest in mathematics and physics and took P. W. Bricigman's famous course in acivancecl thermodynamics. Jeffries's research career indicates that he hac! a solic! foun- ciation in thermodynamics en cl a remarkable aptitude for it. {effries Wyman en cl John T. Ecisall entered Harvard at the same time en c! by their thirc! year hac! clevelopec! a close friendship that lastecl over 75 years. John Ecisall's descriptions of {effries's life are wonclerful sources of infor- mation about their interacting lives.) 2 After graduation {effries spent 1923-24 in Harvard Graclu- ate School taking acivancecl courses in physics en cl chemistry. In June 1924 Jeffries Wyman en c! John Ecisall went abroac! together on a slow steamer with 700 cattle en cl 200 human passengers to work in the newly establishecl Department of Biochemistry in Cambridge, England, headed by Sir Frederick Hopkins ("Hoppy"~. The reader was J. B. S. Haldane, who at that time was writing his book Enzymes on the basis of the course he was teaching. This was just at the time at Cambridge when G. S. Aciair was establishing for the first time the molar mass of hemoglobin en cl was formulating the basic equation for the bincling of oxygen en c! other ligancis to hemoglobin. At the end of one term {effries movecl to London because he became interested in the work on the dynamics of muscle that was being carrier! out by A. V .

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J E F F R I E S WYM A N 365 Hill. In 1926 Jeffries receiver! a Ph.D. from University College for his thesis on the viscoelastic properties of muscle en cl the thermodynamics of muscle contraction. Jeffries became a member of the Biology Department at Harvard in 1927 en cl continual his teaching en cl research there until 1951. In his first years at Harvard {effries spent a large part of his time in the Laboratory of Physical Chemistry, which E. I. Cohn hacl establishecl at the meclical school. His first research there was on the viscosities of protein solutions en c! on the clielectric constants of solutions of clipolar ions. He showocl that the clielectric increment was 23 for oc-amino acids, 71 for clipepticles, en cl Il5 for tripepticles. Ecisall2 writes that Jeffries's ciata on polar liquicis stimulate cl Lars Onsager to pro cluce the first acloquate the ory of the clielectric properties of polar liquicis. Jeffries marries! Anne Cabot in 192S, en c! they hac! two chilciren: Anne Cabot (1929) en cl {effries, {r. (1930). When his wife died of Hodgkins lymphoma in 1943, Jeffries was clevastatecI. He marries! Rosamonc! Forbes in 194S, but that marriage lastecl only IS months. In June 1950 {effries was en route to Korea to give sci- entific lectures, but the Korean war broke out when he reached Japan, and so instead he spent six months in Gen- eral Douglas MacArthur's postwar Japan. Within a couple of clays Jeffries was invites! to visit the emperor, who was interested in biology en cl collectecl invertebrate animals near his summer palace. His ciaughter's books contains the letters he sent to Anne en c! Jeff. B. German en cl I. Wyman (1937) stucliecl the acicI-base titration of deoxy- and oxyhemoglobin and confirmed and extenclec! earlier work that hac! shown that oxygenation of hemoglobin results in the release of hydrogen ions. I. B. S. Haldane and L. J. Henderson had already pointed out the reciprocal relations involvecI, but German en c! Wyman pro-

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366 B I O G RA P H I C A L EMOIRS violet! a more mathematical treatment of the ciata by show- ing that it is possible to calculate the oxygen affinity as a function of pH from these titration curves by an integra- tion. They gave a general treatment of the fact that the effect of oxygenation in increasing the acid dissociation constant of hemoglobin in the alkaline loop implies a reciprocal effect involving a decrease of oxygen affinity with hydrogen ion concentration in the same region. These effects are reversed in the acid loop. In 1939 Jeffries wrote a classic paper that clealt with the heat of oxygenation of hemoglobin, which varies with the pH over the range 3 to Il. He cliscoverecl the important fact that the heat is the same for each stage of the oxygen- ation process, as is the shift in the amount of base bouncl at constant pH. {effries also macle oxiciation-recluction measure- ments (1941~. They clerivec! the relation between the bincling polynomial and the average number of ligands bound by a protein, which was a totally new result. This relation playocl an important role in future theoretical treatments of liganc! binding. They showocl that this same treatment couIcl be appliecl to oxiciation-recluction equilibria. In 1944-45 {effries Wyman was away from Harvard working for the Navy on problems of sonar en cl smoke screens. In 1948 Jeffries published a very complete review of all aspects of the knowledge about heme proteins. It contains a deep analysis of the nature of linked functions as applied to a highly integrated system such as bloocI. Only a small part of this review is on the quantitative thermodynamics of the linkocl functions of these molecules. In the section on linkocl functions Wyman showocl his sophistication in math- ematics en c! thermodynamics, he user! calculus to discuss the variation of the heat of oxygenation with pH. In 1951 Wyman and D. W. Allen began the process of explaining the oxygen equilibrium of hemoglobin and the

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J E F F R I E S WYM A N 367 Bohr effect in terms of structural effects. They concluclec! that the interaction is clue to entropy effects, because the heat effect is the same for each stage of the four-step oxygenation process, whereas the free energy change clue to the heme interactions certainly cliffers markocIly from one step to the next. They suggested that configuration effects involving entropy changes conic! provicle an expla- nation of heme-heme interactions en cl the Bohr effect. This paper was revolutionary in its proposal that cooperative inter- actions among the subunits of hemoglobin conic! be mecliatec! inclirectly by conformational transitions. Wyman en cl Allen hacl cle facto cliscoverecl allostery many years before Jacques Monoc! en c! Francois Jacob of the Pasteur Institute in Paris formulatecl en cl publicizecl the concept as we know it tociay. Remarkably, the paper was cleniecl publication in several other journals before it finally appeared! in the Journal of Polymer Sciences Even tociay, very few biophysicists en cl biochemists are fully aware of the contribution that this seminal work hac! in the clevelopment of allosteric theory. {effries resigned from Harvard in 1951 to be science attache in the U.S. Embassy in Paris from 1952 to 1955. He traveler! wiclely in France visiting scientific laboratories. This was a clifficult time for international scientific relations. Because of the reckless accusations of Senator Joseph McCarthy about Communist infiltration, it was clifficult for foreign scientists to visit the Unitecl States cluring this period. {effries workocl on behalf of a number of French colleagues. In 1954 Jeffries marries! Olga Locligenski, en c! they mover! to Cairo in 1955. {effries was one of the first science attaches in a U.S. embassy. In 1955-58 {effries was director of one of the four regional science offices of UNESCO. His heacI- quarters were in Cairo, but his responsibilities extenclecl from Morocco to Pakistan.

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368 B I O G RA P H I C A L EMOIRS Jeffries was a great walker en c! was quite adventurous. On a vacation trip to western Pakistan he walkocl into a part of Afghanistan that was closecl to foreigners. The local chief- tain cleciclec! that Jeffries must return to Pakistan, en c! so, accompanied by a boclyguarcI, he rocle a yak to the borcler. During the time he was carrying out these aciministra- tive responsibilities, Jeffries continues! to collaborate with John Edsall by mail, by visits to Cambridge, and by John's trips to Europe as they wrote their book Biophysica] Chemistry (1958~. This book hac! its origins in the course they hac! taught together in the Biology Department. It was the first book in an emerging fielcl en cl really clefinecl a cliscipline that remains a centerpiece of moclern macromolecular sci- ences. The plan was to write a second volume, but that was never completecl because John became the editor of the Journal of Biological Chemistry en c! Jeffries went to Rome. When {effries completecl his service to UNESCO, John Kencirew, then director of studies at Peterhouse, invited him to Cambridge for the fall term of ~ 959-60. EraTclo Antonini, from the University of Rome's Biochemical Insti- tute en cl the Istituto Regina Elena, lecturecl at Cambridge en c! invites! Jeffries to visit his department, which was heaclec! by Alessanciro Rossi Fanelli. When they offered {effries a position as guest scientist, he accepted for a "trial periocI" that laster! 25 years. While in Rome, {effries clevelopecl fully the theory of linkocl functions en cl reciprocal effects in his lancimark 1964 paper in Aclvances in Protein Chemistry Using straightforward thermodynamic principles embocliecl by the first en cl second laws, {effries showocl that the responses of a macromolecular system to chemical and physical variables like chemical potentials, pHs, and temperature, are mutually dependent. Linkage relations, formally equivalent to those developed by James Clerk Maxwell in electromagnetism and by Bridgman

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J E F F R I E S WYM A N 369 in his general thermodynamic tables, emerges! from con- sicleration of the nature of the bincling polynomial clevel- opecl in early studies. Never before hacl the power of ther- modynamics, as applied to biology, been so eloquently and elegantly presented to the scientific community. The effects of temperature en cl pH on the oxygenation properties of hemoglobin became intuitively obvious when Tookoc! at through the powerful formalism of linkage thermodynamics. In 1965 Wyman linked the binding polynomial to the concept of the bincling potential as a useful too! for the stucly of ligancl bincling by a polyfunctional macromolecule. This article starts out with, In the course of reading over the other day, at a window by the sea, the page proof of an article on linkage I was suddenly struck by the realization that in all the years I had been thinking about the matter I had consistently failed to recognize one significant general concept, although it is clearly implicit in almost every earlier discussion and stands out unmistakably once it catches the eye. This is the concept of what may be called the binding potential. Wyman usecl the Russian L for the bincling potential to avoid confusion with symbols current for the other more familiar thermodynamic potentials U. S. H. A, en c! G. (Later Alberty4 usecl G' for a similar thermodynamic potential at specified pH en cl pMg, en cl Di Cera5 showocl that the bincI- ing potential is the same as the chemical potential of the reference system.) This was a very important step because it connected Wyman's previous work more closely with the formulation of the rest of thermodynamics of reaction systems. He pointed out that thermodynamic potentials "are not accessible to measurement but are known only in terms of their changes." He further notes! that "every liganc! may be expected to exert some influence on every other, in other words, that, at the highest level of approximation the ligands all form a single linkage group. The breaking up of this

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370 B I O G RA P H I C A L EMOIRS group at a Tower level of approximation clepencis on the factorability of the polynomial." In 1985 John Ecisalli wrote, "Certainly in moclern times it is most unusual, if not unprececlentecI, for a scientist to leave research for as long as eight years, becoming cleeply involvecl in other responsibilities, en cl then return to sci- ence, en c! make his most important research contributions in the years that followocI. Yet that is, in fact, what {effries achieved." During his time in Rome {effries further clevel- opec! the concept of allosteric linkage, introclucec! Legencire transforms en cl bincling potentials to the fielcI, en cl cliscussecl polysteric and polyphasic linkage. Jeffries hac! become well acquainted! with Jacques Monoc! while he was in Paris in 1952-55. Now Monocl en cl his group were working on regulatory aspects of metabolism, and especially feedback inhibition of metabolic nathwavs. Monod ~ ~ ~ ~ . ~ 1 J anct Jacob nact ~ntroctucecl the term "allosteric" in 1961 to describe enzymes that can bincl effecter molecules at sites quite distinct from the catalytic site. The bincling of the effecter incluces conformational changes that promote or inhibit catalytic activity. When {effries visited Paris in 1964, Jacques Monoc! invites! him to give a seminar on his views about the effects of conformation changes in hemoglobin on ligand binding and their relation to cooperativity and effecters. These discussions lee! to the famous paper by Monod, Wyman, and Changeux (1965) proposing that al- losteric proteins are oligomers, composed of several sub- units (protomers), the oligomer being capable of existing in two distinct conformations, clenotecl as T en cl R. which differ in their affinity for ligancis en cl effecters. Homotropic interactions are always cooperative, en c! heterotropic inter- actions, which are causecl by clisplacement of the R/T equi- librium by the effecter, can involve either activation or in- hibition at the catalytic site for an enzyme or at the

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J E F F R I E S WYM A N 371 ligancI-bincling site for hemoglobin. Later Jeffries wrote a tribute to Jacques Monocl ~ ~ 979) that describes the writing of this paper, which was such a stimulus to the fielcI. In 1967 Jeffries wrote a paper for the Journal of the American Chemical Society that presented a detailed dis- cussion of the equations involvecI. In this paper Wyman uses the term "allosteric bincling potential." Wyman user! the term to describe regulatory effects clue to conformation changes in a macromolecule inclucecl by the bincling of a ligancI. Allosteric equilibria always leac! to positive homotropic interactions. This paper discusses in cletail the many equa- tions involvecI. In 1968 Wyman wrote a complete review of regulation en cl control in macromolecules. In his conclucling remarks {effries raises the questions, "Why is it, from a molecular point of view, that the different conformations shouic! have different ligancl affinities, en cl why is it that the uptake of ligancl shouIcl leacl to a conformation change?" He con- clucles his review with the comment that "these en c! other problems of structure en cl function lie in the Biophysics en cl Biology of tomorrow." In 1975 he wrote a mathemati- cal paper showing that the binding of ligands by a macro- molecule can be clescribecl by an Abelian group of thermo- clynamic potentials. Each member of the group corresponds to a particular set of experimental conditions: system open to some, closecl to others of the ligancis. The group of ther- moclynamic potentials provides all possible linkage relations, en c! various thermodynamic potentials can be clerivec! from each other by Legendre transforms. Here Wyman provides a clear description of how different choices yielcl different information, and he also introduces the distinction between true en cl pseuclolinkage This was an important generaliza- tion of the unclerlying theory. In ~ 98 ~ Jeffries wrote "The Cybernetics of Biological

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372 . B I O G RA P H I C A L EMOIRS Molecules," which clealt with ligancI-inclucec! association, clis- sociation, or phase changes, so-callecl polysteric reactions. This provides a broacl overview of the thermodynamics of bincling en c! of linkage mechanisms. Linkage uncler steacly state conditions en cl free energy transduction are cliscussecI. In 1984 Careri and Wyman wrote a paper entitled "Soliton- Assistec! Uniclirectional Circulation in a Biochemical Cycle." Beginning in 1964 while {effries was in Rome he was nvolvecl in the establishment of the European Molecular Biology Organization (EMBO). He was the first secretary- general, a member of the Council, en cl at some time or other a member of almost every committee establishecl by the Council. EMBO establisher! the European Laboratory of Molecular Biology, which was heaclecl by John Kencirew. After about 1975 {effries macle yearly trips to Stanley Gill's laboratory at the University of Colorado. When they started writing a book together in 1979, {effries was suffer- ing increasingly from Parkinsons' disease. In 1980 they pub- lishec! together on sickle cell hemoglobin. Because this hemoglobin has a tendency to precipitate out of solution, they hacl to clevelop polyphasic linkage. While {effries was going back en c! forth between Rome en c! Bouicler, he was working on a long paper on linkage graphs, which appeared in 1984. In this important article he acknowlecigecl many discussions with Stanley Gill, en c! P. E. Phillipson (Physics Department, University of Colorado) and expressed his ap- preciation to Eralclo Antonini, whose recent untimely cleath had left such a gap. In 1985 Gill, Richey, Bishop, and Wyman emphasized the use of the binding partition function in generalizing binding phenomena in an allosteric macro- molecule. In 1987 Robert, Decker, Richey, Gill, and Wyman generalized the allosteric model that incorporates a hierar- chy of conformational equilibria. In 1988 Di Cera, Gill, and

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J E F F R I E S WYM A N 373 Wyman publisher! their canonical formulation of linkage thermodynamics. In 1990 Wyman en cl Gill brought all this together in their book Bin cling en c! Linkage: Functional Chemistry of Biological Macromolecules Their iclea was to bring together in one place concepts en cl procedures applicable to ligancl bincling by biological macromolecules en c! to show from what minimum set of general physical en cl mathematical principles they arise. This book remains a cornerstone of moclern biophysical chemistry en c! is wiclely user! in graclu- ate courses in biochemistry en cl biophysics. In his paper on linkage graphs (1984), Jeffries looked to the future when rate processes en c! quantum mechanics wouIcl have to receive more attention in unclerstancling bincI- ing phenomena. He then commented that his emphasis on thermodynamics hac! been clue to "the commancling role of thermodynamics as a limitation to which all natural processes are subject, a common background shared by all dynamical phenomena." He also quoter! Emilio Segre6 who wrote, Thermodynamics has the same degree of certainty as its postulates. Reason- ing in thermodynamics is often subtle, but it is absolutely solid and conclusive. We shall see how Planck and Einstein built on it with absolute trust and how they considered thermodynamics the only absolutely firm foundation on which to build a physical theory. Whenever they were confronted by formidable obstacles, they turned to it. When Jeffries was 83 this magnificent paper was pub- lishecI, en c! so some philosophical comments were certainly justified. {effries once toIcl one of us (E.D.C.), "Never yielcl to temptation, unless it persists." Thermodynamics was his lifelong temptation en c! Wyman's monumental contribution was to bring the rigor of thermodynamics to biochemistry. In 1986 {effries en cl Olga movecl to Paris en cl livecl in the Paris flat that Olga's parents bought in 1945. In Paris

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374 B I O G RA P H I C A L EMOIRS Jeffries continues! his scientific work en c! publisher! on nesting in 1987 en cl the canonical formulation of linkage thermo- clynamics in 1988. {effries en cl Olga hacl a summer place near Sens, where Jeffries wouic! enjoy hour-Ion" afternoon walks in the countryside. Olga cliecl in 1990. {effries cliecl in his sleep on November 4, 1995. His funeral was helcl in the Russian Orthodox Church at Saint Genieve en Bois outsicle Paris. There was a memorial service for him at the Bigelow Chapel at the Mount Auburn Cemetery, Cambridge, Massa- chusetts, on December Il. 1995. WE ARE INDEBTED to Anne Cabot Wyman for her assistance in writing this biographical memoir. NOTES 1. T. T. Edsall. Teffries Wyman and myself: A story of two interacting lives. In Comprehensive Biochemistry, vol. 36, ed. G. Semenza, chap. 3. Oxford, UK: Elsevier, 1985. 2. T. T. Edsall. Teffries Wyman, philosopher and adventurer. Biophys. Chem. 37 ~ 1990) :7-14. 3. Anne Cabot Wyman. ieffries Wyman: Letters from Japan 1950. Cam- bridge, Mass.: Fleming Printing, 2000. 4. R. A. Alberty. Thermodynamics of Biochemical Reactions. Hoboken, N.T.: Wiley, 2002. 5. E. Di Cera. Thermodynamic Theory of Site-Specific Binding Processes in Biological Macromolecules. Cambridge, UK: Cambridge University Press, 1995. 6. E. Segre. From X-rays to Quarks. San Francisco: Freeman, 1980.

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J E F F R I E S WYM A N SELECTED BIBLIOGRAPHY 1937 375 With B. German. The titration curves of oxygenated and reduced hemoglobin. 7. Biol. Chem. 117:533-50. 1939 The heat of oxygenation of hemoglobin. 7. Biol. Chem. 127:581-99. 1941 With E. N. Ingalls. Interrelationships in the reactions of horse hemoglobin. 7. Biol. Chem. 139:877-95. 1948 Heme proteins. Adv. Protein Chem. 4:407-531. 1951 With D. W. Allen. On hemoglobin and the basis of the Bohr effect. 7. Polymer Sci. 7:499-518. 1958 With J. Edsall. Biophysical Chemistry. New York: Academic Press. 1964 Linked functions and reciprocal effects in hemoglobin: A second look. Adv. Protein Chem. 19:223-86. 1965 The binding potential, A neglected linkage concept. 7. Mol. Biol. 11:631-44. With J. Monod and J. P. Changeux. On the nature of allosteric transitions: A plausible model. 7. Mol Biol. 12:88-118. 1967 Allosteric linkage. 7. Am. Chem. Soc. 89:2202.

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376 B I O G RA P H I C A L 1968 EMOIRS Regulation in macromolecules as illustrated by haemoglobin. Q. Rev. Biophys. 1: 35-80. 1975 A group of thermodynamic potentials applicable to ligand binding by a polyfunctional macromolecule. Proc. Natl. A cad. Sci. U. S. A. 72: 1464-68. The turning wheel: A study in steady states. Proc. Natl. Acad. Sci. U. S. A. 72:3983-87. 1979 Recollections of Jacques Monod. In Origins of Molecular Biology: A Tribute to facques Monod, eds. A. Lwoff and A. Ullman, pp. 221-24. New York: Academic Press. 1980 With S. J. Gill. Ligand-linked phase changes in a biological system: Applications to sickle cell hemoglobin. Pro c. Natl. A cad. Sci. U. S. A. 77:5239-42. 1981 The cybernetics of biological macromolecules. Biophys. Chem. 14:135-46. 1984 Linkage graphs: A study in the thermodynamics of macromolecules. Q. Rev. Biophys. 17:453-88. With G. Careri. Soliton-assisted unidirectional circulation in a bio- chemical cycle. Proc. Natl. Acad. Sci. U. S. A. 81:4386-88. 1985 With S. J. Gill, B. Richey, and G. Bishop. Generalized binding phenomena in an allosteric macromolecule. Biophys. Chem. 21:1-14. 1987 With C. H. Robert, H. Decker, B. Richey, and S. J. Gill. Nesting: Hierarchies of allosteric interactions. Proc. Natl. A cad. Sci. U. S. A. 84: 1891-95.

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J E F F R I E S WYM A N 1988 377 With E. Di Cera and S. J. Gill. Canonical formulation of linkage thermodynamics. Proc. Natl. Acad. Sci. U. S. A. 85:5077-81. 1990 With S. J. Gill. Binding and Linkage: Functional Chemistry of Biological Macromolecules. Mill Valley, Calif.: University Science Books.