Those of us who had the privilege of working at Caltech during those years refer to that period as the Golden Age. Apart from the great Linus Pauling, there was a U.S.A. select team in structural chemistry: Verner Schomaker, Eddie Hughes, Robert Corey, Jerry Donohue, Kenneth Trueblood, Gene Carpenter, Ken Hedberg, David Shoemaker, Alex Rich, Dick Marsh, besides a stream of post-docs from outside the U.S.A.; Gunnar Bergmann from Sweden, Otto Bastiansen from Norway, Edgar Heilbronner from Switzerland, Massimo Simonetta from Italy, You-chi Tang from China, all in the first period, John Rollett, David Davies, Leslie Orgel, all from England, Giovanni Giacometti from Italy in the second. Among the graduate students were Walter Hamilton, Doyle Britton, Martin Karplus, Jim Ibers, Hans Freeman, Berni Alder and Joe Kraut. All of these became future leaders in structural chemistry and cognate areas of research.
Right from the start it was obvious to me that my Caltech colleagues had a much better background in theoretical crystallography, diffraction physics and mathematics than I had; even the graduate students seemed to know more about these matters than I had learned in my five years of practice at Glasgow and Oxford. I saw that one of my first priorities would be to establish a more solid base in these subjects for myself. Fortunately for me, my new colleagues were generous in sharing their knowledge.
The cyclobutane structure was to be my major research task. Verner arranged with colleagues in Berkeley for a small cylinder of the material to be delivered to us. Meanwhile, he and Kenneth Hedberg introduced me to the theoretical and experimental aspects of gas-phase electron diffraction. I shall not dwell here on these, except to mention the curious fact that our visual estimation of the scattered intensity was actually based on an optical illusion. The diffraction patterns, recorded on photographic plates, appeared to the eye to consist of a set of concentric rings of gradually decreasing intensity. According to photometric measurement, however, the scattered intensity showed a monotonic decrease from the film centre outward, with no outspoken maxima or minima. The eye automatically compensates for uniform intensity fall-off and interprets differences in the rate of change between neighboring regions of the film as local maxima and minima. The first step for the novice was to learn to translate the visual experience of rings of high and low intensity into a physically interpretable diffraction pattern. This was achieved by looking at photographic diffraction patterns from diatomic molecules (chlorine, oxygen) until one "saw" the intensity variation predicted by theory: a set of equidistant rings corresponding to the single frequency produced by the single interatomic distance. After a few months I was admitted into the small, select circle of people whose opinion about features on electron diffraction photographs was deemed to matter, and, by the end of the year, as a prelude to the planned cyclobutane analysis, I was immersed in the interpretation of photographs obtained previously for cyclopropene. Then I helped Hedberg to redetermine the structural parameters of the triatomic molecules ClO2 and Cl2O. (15) It is remarkable how well our results derived by such primitive methods compare with those from analyses made many years later with more up-to-date equipment.
Our gas-phase electron-diffraction study of cyclobutane (16) confirmed my supposition that the C—C bonds were long. Moreover, contrary to what had been generally assumed until then, the four-membered ring was not a planar square but was buckled (D2d rather than D4h symmetry). The reason for the striking difference between the carbon-carbon bond distances in cyclopropane (1.51 Å) and cyclobutane (1.57 Å) is that in the former there are no non-bonded 1,3-interactions, whereas the four-membered ring shows the strongest possible interactions of this type, which are, of course, strongly repulsive. It was a great experience to work with Verner Schomaker, to argue with him, and, more than anything, to share with him the writing of a scientific paper. Our cyclobutane paper took ages to write, but, as compensation, after almost 50 years, I am still pleased with the result. Among other things, that publication contained what must have been one of the earliest force-field calculations, and also a carefully qualified sentence defining what we meant by the term "bent bond:"
"It appears that this argument might be expressed in terms of the significant existence of a bond line, to be distinguished from the internuclear (straight) line, which more or less follows a line of maximum density of the bonding electron distribution, and which, in the bent bond, tends to retain a fixed length, thereby possibly causing the internuclear distance to be shortened in spite of the resulting increased internuclear repulsion."
More than thirty years later, when bent bonds had become fashionable and had showed up in Bader's theory of chemical bonding, this definition received a seal of approval when it was reproduced in one of Bader's papers (17) - although without the commas over which we had deliberated so long. Not many sentences in the scientific literature are deemed to be worth repeating after thirty years.
Apart from my work in the chemistry laboratories, I spent a fair amount of time with members of Max Delbrück's phage group, especially with Gunther Stent, Carleton Gajdusek, Jean Weigle and Elie Wollman. A feature of this group was the active social life enjoyed by its members. In addition to frequent parties at the Delbrück home, there were regular expeditions to destinations in the nearby California deserts and mountains. After driving along perilous dirt-roads until a suitable camp-site was reached, we cooked our meals on an open fire, drank copious amounts of cheap, sold-by-the-gallon wine, and slept under the brilliant stars. Topics of discussion around the campfire were not restricted to scientific ones; they included such matters as the superiority of Mozart over Wagner, the authorship of Shakespeare's plays, mathematical puzzles (such as the generalized cake problem), and many, many others.
Among these was the fundamental problem: How do living organisms manage to make copies of themselves? How is the organizational information stored and transmitted down the generations? Of course, we did not know the answer. It must have been early in 1949 when Delbrück told me that in his opinion my work in structural chemistry was a waste of time. He proposed that I should abandon it and join his research group instead; the switch to phage work would provide an entrance into the world of biological research and enable me to use such talents as I possessed to better purpose. I was dismayed that Delbrück thought so little of my work in chemistry but at the same time flattered that he saw me as having potential for creative research in his own area, for he was known to have extremely high intellectual standards. After a couple of weeks I decided not to accept his offer. I felt I had just reached the stage in my own development where I was reasonably competent in at least one area of research; I knew where the good problems lay and I knew I could solve them as well as anyone else. Having just reached that stage, I was unwilling to start again as a novice in a field where I was essentially ignorant. I did not want to be an eternal student, at least not only an eternal student.
I recalled this decision nearly twenty years later, when Delbrück sent me a copy of the Festschrift “Phage and the Origins of Molecular Biology” dedicated to him on his 60th birthday. (18) By that time the revolution in molecular biology had occurred, and Max was being celebrated as one of its founders. I wrote to express my appreciation that he had once thought of me as a potential collaborator and reminded him of his offer and of my reasons for declining it. I told him I had no regrets; I felt I had made the right choice and I still do so.
I have never regarded Delbrück as one of the fathers of molecular biology. In fact, in those days it was my impression that he was rather hostile to the ideas behind molecular biology. As I recall, he sat beside me at the lecture where Pauling first publicly announced his stable hydrogen-bonded model structures for polypeptide chains. Pauling had a feeling for drama. On the table in front of him stood bulky columnar objects shrouded in cloth, which naturally excited the curiosity of those in the packed auditorium. Only after describing in detail the structural principles behind the models did he turn to the table and unveil the molecular models with a characteristic theatrical gesture. There were the two structures, the three-residue and the five-residue spirals, later dubbed the α- and γ-helices! I was immediately converted, a believer right from the start. In contrast, Max made no secret of his skepticism and especially his disapproval of Pauling's manner of presentation, and asked if I thought there was anything of value in these models. I believe I may have disappointed him when I told him that in my opinion the models were based on sound structural principles and were very likely to represent important building blocks of actual proteins.
While my own work at Caltech had nothing to do with protein structure, Pauling used to talk to me occasionally about his models and what one could learn from them. In his lecture, he had talked about spirals. In conversation a few days later, I told him that for me the word "spiral" referred to a curve in a plane. As his polypeptide coils were three-dimensional figures, I suggested they were better described as "helices." Pauling's erudition did not stop at the natural sciences. He answered, quite correctly, that the words "spiral" and "helix" are practically synonymous and can be used almost interchangeably, but he thanked me for my suggestion because he preferred "helix" and declared that he would always use it henceforth. Perhaps he felt that by calling his structure a helix there would be less risk of confusion with the various other models that had been proposed earlier. In their 1950 short preliminary communication, Pauling and Corey wrote exclusively about spirals, (19) but in the series of papers published the following year (20) the spiral had already given way to the helix. There was no going back. A few years later we had the DNA double helix, not the DNA double spiral. The formulation of the α-helix was the first and is still one of the greatest triumphs of speculative model building in molecular biology, and I am pleased that I helped to give it its name.
The structural chemistry group at Caltech was among the first to use punched-card methods to ease the computational problems of crystal structure analysis. We could complete a three-dimensional structure factor calculation or Fourier synthesis for a small-to-medium organic structure overnight instead of over a period of weeks. During my first stay at Caltech I made a simple program for two-dimensional least-squares analysis in space group P21/a, and during my second stay I helped John Rollett to write a general least-squares program, including refinement of "thermal" as well as positional parameters, for the impressive sounding Electrodata Datatron, an early electronic computer, which we were allowed to use after normal office hours, that is, during the night, from evening until early morning. My contribution to this was quite modest. John wrote the program code during the day, and I called the numbers out to him in the evening as he typed them onto a tape. Together we worked on the crystal structure of dibenzyl phosphoric acid. Our objective was to determine the geometry of the phosphate di-ester group for comparison with the dimensions assumed in the Crick- Watson DNA model. (21) Nowadays, we would describe the C-O-P-O-C conformation in terms of the two C-O-P-O torsion angles, but at that time the utility of torsion angles as conformational descriptors had not yet come into general usage. At any rate, torsion angles are not mentioned in our paper. (22) Instead we discussed the dihedral angle between the two POC planes. We wrote then that the value of this dihedral angle "is 88° in dibenzyl phosphoric acid but only 63° in the Crick-Watson model" and proceeded to give an explanation of this difference "in terms of van der Waals repulsion between the phosphate group and the deoxyribose ring."
It is embarrassing to admit that we must have made a mistake in calculating the value of the dihedral angle in our structure. The correct value, based on our published atomic coordinates, is 65°, practically the same as the assumed Crick-Watson value. After so many years, I cannot remember how we calculated the value of this dihedral angle, nor can I find any record of how it was done. Presumably, one of us made the calculation and the other checked it, so we are both to blame. But before anyone censures us for having made such a grievous mistake, she should set herself the task of evaluating the dihedral angle in question with paper and pencil, without even the aid of a hand calculator, from the atomic coordinates and unit cell dimensions listed in our paper. As I recall, it was only years later in Zurich when we began to work on medium ring compounds that we began to use torsion angles systematically to describe the ring conformations and developed simple algorithms for calculating dihedral angles.
During my first stay at Caltech I was best known there not for any scientific accomplishments but for my collaboration with Ted Harrold, an English postdoc in George Beadle's research group, in writing and producing cabaret-style entertainments. Ted was an accomplished pianist who could improvise for hours in almost any style from Bach to Honkytonk, and we soon found a mutual fascination with the radio commercials that were so characteristic of popular culture in America at that time and a shared amusement in inventing parodies of them. Mostly we set new words to well known tunes, but Ted also set some of our new words to music of his own. We thought the results were funny, and perhaps they were. Somehow or other, Beadle got to hear of this, and we were ordered, or let us say strongly encouraged, to organize an entertainment for the 1948 Departmental Christmas Party. Within a few weeks, we assembled enough material for a forty-minute cabaret and persuaded a few other people to join us in the songs and choruses. We asked our audience to imagine that radio commercials had been taken over for an evening by scientific and academic institutions eager to advertise their wares. The show included commercials from Harvard, Yale, Chicago, Caltech, the Sorbonne and even Oxford and Cambridge, as well as from manufacturers of scientific equipment. It was a great success and parts of it were later recorded. Ted and I produced shows for the two following Christmas Parties, in 1949 and 1950. These were probably not as successful as the first, although the 1950 production, a much debased parody of Marlowe's Dr. Faustus, had some good lines in it.