“There’s a huge amount of sequence space that evolution never touched.” all sorts of things from them,” he says. Bradley wants to use his toroidal proteins to make artificial channels in membranes and as scaffolds for presenting other proteins or peptides. The designed proteins are stable enough that they should tolerate the insertion of other peptide sequences— ones researchers want displayed—into the loops without compromising the overall architecture, Bradley says. Andreas Plückthun, a protein researcher at the University of Zurich, points out that neither of the teams has yet made proteins that can bind other biomolecules. Such proteins have many biochemical applications, including use as probes. So until the teams present such a design, “the general significance of the work will remain somewhat limited for those outside the protein design community,” he says. But, says Ingemar André, who designs proteins at Lund University, “both studies demonstrate that it is possible to design proteins with conformations not found in nature. The full repertoire of repeat proteins has not been fully explored in evolution, and novel types of assemblies can be engineered.” Baker agrees: The papers “really demonstrate that what you see in nature is a very small fraction of what’s possible. You can sort of see it from the numbers game. For a 200-amino acid protein, there are 20200 different sequences. You can argue that 1010 or 1012 have been sampled during evolution. We know there’s a huge amount of sequence space that evolution never touched.” ◾
JEFFREY I. SEEMAN C&EN talks with the CHEMISTRY HISTORIAN about R. B. Woodward and Roald Hoffmann’s Nobel Prize-winning collaboration BETHANY HALFORD, C&EN BOSTON
FOR ORGANIC CHEMIST and chemistry
historian Jeffrey I. Seeman, questions are like seeds. Once one is planted in his mind, it tends to flourish, leading him to ask many more questions and publish a multitude of related research papers. In his latest publication, Seeman, a scholar at the University of Richmond, explores how the kernel of an idea blossoms into Nobel Prize-winning work. The paper, which totals more than three dozen pages in the Journal of Organic Chemistry, examines the time period from May 5, 1964, to Nov. 25, 1964, when organic chemist Robert Burns Woodward and theoretical chemist Roald Hoffmann began their Seeman famous collaboration (2015, DOI: 10.1021/ acs.joc.5b01792). During this time, the pair wrote their first paper on what would eventually become the Woodward-Hoffmann rules, which predict the outcome of certain reactions based on molecular orbital symmetry. The landmark theoretical work earned Hoffmann a share of the 1981 Nobel Prize in Chemistry. Scholars agree Woodward would have also received the honor (it would have been his second Nobel Prize) had he not died in 1979. As he lays out in his paper, Seeman finds that the process that took Woodward and Hoffmann from idea to groundbreaking theory was not the all-consuming effort one might expect. Rather, it was a route filled with diversions. Seeman recently sat down with C&EN to talk about the paper’s genesis and his work. CHEMICAL HERITAGE FOUNDATION
solved X-ray crystal structures of four representative left-handed proteins. Even though no left-handed closed repeating proteins have been observed in nature, Bradley thinks some are out there waiting to be discovered. “Based on our results, there’s not any strong protein biochemistry reason you can’t have left-handed helical bundles that close up,” he says. Bradley and Baker both hope to use their repeat proteins to design new materials. “Imagine materials that are built from rods and nodes from which those rods protrude,” Baker says. His team’s designed proteins would be the rods. “We now have a variety of ways of sticking these rods together into nodes. We’re starting to build
What got you interested in a project about how the WoodwardHoffmann rules came about? CEN.ACS.ORG
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The “project” is actually a series of 15 or possibly more papers focused on the development of organic chemistry from the 1950s to 1970s through the lens of the development of the WoodwardHoffmann rules. To a large extent the idea originated with the 2004 assertion by Harvard University organic chemist E. J. Corey that there was plagiarism involved in the origin of the Woodward-Hoffmann rules research. [Editor’s note: Corey contends that he offered an idea to Woodward that led to the rules and was never credited.] I was interested in examining that claim. As I looked at that claim more and more, I realized that was only a slice—a small but very important slice—of a very large picture dealing with how science develops. How did this idea—about the development of a scientific idea— and others come together into the JOC paper? Historians, like all researchers, gather data. One critical piece of data was the laboratory notebooks of Roald Hoffmann. As I studied those, it became immediately clear that there was no direct path from May 5, 1964—the date that Hoffmann records the beginning of his collaboration with Woodward—to Nov. 25, 1964, when their first paper was submitted to the Journal of the American Chemical Society. I wanted to know: Why was there not a direct path? What were the other things that were going on in Woodward’s and Hoffmann’s lives? How did it all transpire? And why? I didn’t know the answers to any of those questions, but they were in the data. They were in the lab notebooks and in the events
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R. B. Woodward circa 1960.
swirling around Woodward and Hoffmann— the people they talked to, the lectures they heard. What was it like to have unfettered access to Hoffmann’s historic notes? On a somewhat superficial, though not trivial, level, it was a blessing for a historian: a gold mine of primary and often otherwise privileged information. But it was more than unfettered access to Hoffmann’s notes. It was unfettered access to Hoffmann, the human being. I have probably over 1,000 e-mails from him. He’s immediately responded to everything I’ve ever asked. Every now and then I ask something I think might be crossing a boundary, and I wonder if I’m going to be told, “That’s not appropriate.” That’s never happened.
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What does it take to do this type of historical research? It takes an enormous amount of data; data collection; data analysis; poring through archives; interviews, either on the phone or in person; thousands of emails; and a tremendous method of organizing my data. All research is demanding. I’ve been working on the Woodward-Hoffmann story for almost 12 years. I’ve already published a few papers that are tangential to the main theme, and I’m working desperately to focus so that CEN.ACS.ORG
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◀ A PORTRAIT OF THE
THEORIST AS A YOUNG MAN Roald Hoffmann in
the mid-1960s.
this series of papers can be completed. What do you hope readers will take away from the piece? The takeaway is how very dependent science is on the human component and how wonderfully interesting that is. The drive for uniformity in scientific publications tends to minimize understanding of the humanism of science. That drive is misplaced. Maybe scientific articles should be broader to include the human component as appropriate. ◾
