Ligand-Receptor Complexes: Origin and Development of the Concept

A few years ago I published a small monograph entitled Ligand-Receptor Energetics (1) and dedicated it to a number of individuals “whose contributions are no longer remembered.” This volume assembles in a logical array the major features of the concepts and procedures developed in the core area of my research interests. Unlike most of my contemporaries, I did not spend a postdoctoral period or a sabbatical leave in the laboratory of a distinguished scientist. Nevertheless, I have profited enormously from shorter periods of contact with some of the extraordinary individuals of the 20th century, including in my younger days, J. Franck, P. Debye, J. D. Bernal, S. Goudsmit, O. Loewy, E. Chargaff, A. Szent-Gorgyi, and M. Kac. From them and others I obtained numerous valuable insights and wise maxims, of which the following are a sampling. J. Franck: “always multiply by a factor of 3 an experimenter’s claim of the uncertainty of his results.” P. Debye: “even when a very prestigious scientist states a “fact,” be cautious.” In an early decade of the 20th century, Debye calculated theoretically what the dipole moment of HCl (I think) is and obtained a value of (let us say) 1.85 (Debye units). The then available experimental value was markedly lower (let us say 1.40). New experimental studies were undertaken, therefore, by a succession of physicists, and these yielded dipole moments progressively closer to 1.85. At this point, for reasons that I have forgotten, Debye was prompted to reexamine his theoretical calculation. Lo and behold he discovered he had made an error in his earlier theoretical computation. When corrected, the theory now led to a dipole moment of 1.40, in agreement with the first experiments, which thereafter were widely confirmed. O. Loewy: “before giving a seminar, it is more important to have an empty bladder than a full mind.” E. Chargaff: “so-called model experiments are carried to incredible lengths prompting one to say that confusion superimposed on complexity may produce papers but not results. [After all] a skunk dipped in chlorophyll is not yet a rose bush.” A. Szent-Gorgyi: “when I first took up fishing, I always used an enormous hook . . . [it is] more exciting not to catch a big fish than not to catch a small one . . . Now I have reduced the size of my hook.” However, these individuals were not the only ones “on whose shoulders I have stood” to attain the understandings I have reached of ligand-receptor interactions. The achievements of the less known men provided the foundations for the creations of their successors, yet their names have largely been lost to succeeding generations. My interest in ligand-receptor interactions was first aroused in 1942 when I read an article by P. H. Bell and R. A. Roblin (2) on the relative effectiveness of a series of sulfa drugs of different structures. From the late fall of 1940 until the spring of 1945, I was fully engaged in a number of wartime research projects established by the National Defense Research ComTHE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 279, No. 1, Issue of January 2, pp. 1–12, 2004 © 2004 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A.

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