Profile of Axel Brunger Xel Brunger Is So Thoroughly Schulten Had Studied for His Ph.D
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PROFILE Profile of Axel Brunger xel Brunger is so thoroughly Schulten had studied for his Ph.D. interdisciplinary that it is hard under the theoretical chemist Martin to pin down exactly what kind Karplus at Harvard. Karplus, who, in of scientist he is. ‘‘Biophysicist’’ addition to his duties at Harvard is di- Awould be a start. He began his career as rector of the Biophysical Chemistry a computational theorist, but in 1998 he Laboratory in Strasbourg, France, trav- jumped into wet-lab molecular biology. eled regularly to Europe. Brunger ob- Deeply involved in protein crystallogra- tained an introduction from Schulten phy, he is expert not only in obtaining and arranged to meet Karplus in at a structures but also in exploring the bio- cafe´in Paris. chemical behavior of large proteins or ‘‘I found the research he was doing complexes, particularly those involved in fascinating,’’ Brunger says. Karplus was transmitting impulses at neural synapses. pioneering computer simulations of But ask any structural biologist who macromolecular systems, much more Brunger is, and you will probably hear detailed studies than Brunger had en- that he is the creator of X-PLOR and countered in his Ph.D. Brunger decided its successor, CNS. These popular soft- to do his postdoctoral studies with Kar- ware packages combine the fundamental plus and won a NATO fellowship to methods of simulated annealing and fund the work. At Harvard, Brunger cross-validation of x-ray diffraction and found not just one, but two mentors: NMR data. Researchers use X-PLOR Karplus and Gregory Petsko, a protein and CNS to produce refined, atomic- Axel Brunger crystallographer, who introduced level structures that reveal the workings Brunger to the type of challenges that of enzymes and molecular machines. structural biologists face with their huge For his own advances, and those he mathematics and quantum theory and sets of data in which clouds of electron has enabled others to achieve, Brunger found it all really interesting,’’ he says. density obscure the position of atoms was inducted into the National Academy He took mathematics and physics tracks within proteins. of Sciences in 2005. His Inaugural Arti- at the University of Hamburg. ‘‘But Brunger spent two years at Harvard cle (1), published in the October 2, 2007 then I did an undergraduate project in before visa regulations required him to issue of PNAS, reports the structure of theoretical physics with Rudolf Haag return to Germany for a year. In this Ufd2p, a ubiquitin ligase that partici- using ‘algebraic’ methods and I found it interlude he spent time at the Max pates in the degradation of misfolded a little too abstract. And that’s when I Planck Institute for Biochemistry near proteins at the endoplasmic reticulum. decided to go into biophysics.’’ Munich, working in the groups of Dieter Axel Brunger was born Axel Bru¨nger He had to look outside Hamburg, Oesterhelt and Robert Huber, who in 1956 in Leipzig, East Germany. (He however. ‘‘Certainly at the time it was pushed him to explain exactly what good dropped the umlaut when he became an really not the most interesting place for his computational methods were doing American citizen in 1991.) His parents biophysics, although this has changed anyone. ‘‘They challenged me to come were both doctors, and even though they now, especially with the major build-up up with something that’s really useful.’’ were making a living of sorts, they de- of the a new light source at Hamburg’s He also met a junior group leader, Marius Clore, who was looking for com- cided the regime was preventing them DESY [Deutsches Elektronen- putational tools to interpret his NRM from advancing because they did not Synchotron],’’ he says. He spent several data. ‘‘And that’s really when X-PLOR want to get involved in the Communist weeks traveling around West Germany was born—it started as a program for Party. meeting with directors of various Max ‘‘They just couldn’t take it anymore,’’ NMR structure determination,’’ he says. Planck Institutes. ‘‘In retrospect I am On his return to Harvard, this time as he says. ‘‘So they decided to escape amazed that I was able to talk with all through Berlin in 1960. My mother and a research associate, Brunger focused on these directors. The only thing I told a problem that Petsko said many x-ray my grandmother and I got a day pass to them is that I had a physics degree. go from East to West Berlin and then crystallographers faced. Determining There were no references or anything we went to the airport and took a plane the structure of a protein from raw elec- like that. Yet I was able to get appoint- to West Germany. And my dad was go- tron density data is a bit like deducing ments and talk with them.’’ ing to a conference in West Germany, where the bones are in the skeleton of a He signed on for a Ph.D. with Klaus so he was able to get permission to do species of fully fleshed beast that one is that. We traveled independently because Schulten at the Max Planck Institute in seeing for the first time. A crystallogra- we didn’t want to arouse suspicion. So Go¨ttingen. Schulten soon received an pher hazards a first guess as to which that’s how we got out of East Ger- offer from the Technical University of amino acid residues the sausage-shaped many.’’ Six months later the Berlin Wall Munich, and Brunger followed along to electron clouds represent and then has went up. complete his degree in 1982. For his to refine the structure to pinpoint the ‘‘We had friends in Hamburg who put dissertation, Brunger developed compu- precise locations of the atoms. us up in their flat for a while until my tational methods to explore how mole- ‘‘For the first time,’’ Brunger says, ‘‘I parents were able to get jobs and rent cules are transported within and across made use of a statistical method to im- their own flat. I grew up in Hamburg,’’ membranes. As part of this work, he developed a method that other scientists he says. In school, what the West Ger- This is a Profile of a recently elected member of the National mans called ‘‘gymnasium,’’ he became could use to analyze data to measure Academy of Sciences to accompany the member’s Inaugural fascinated by abstract mathematics and the mobility of proteins in lipid Article on pages 15599–15606 of volume 104. physics. ‘‘I read a lot about applied membranes. © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806286105 PNAS ͉ August 5, 2008 ͉ vol. 105 ͉ no. 31 ͉ 10643–10645 Downloaded by guest on September 23, 2021 prove the fit with the diffraction data.’’ about the entire system. ‘‘If you take out colleagues, actually having a wet lab,’’ Brunger termed his concept, which he one data point, and compute an image he says. An initial collaboration with introduced in a 1987 Science paper (2), with that point left out, you won’t notice one of his Yale colleagues, Lynne ‘‘simulated annealing refinement’’ (re- any difference in the image. Now, if you Regan, led to them solving the structure ferring to the metallurgical technique of take out 10%—and you randomly select of a class of coiled-coil proteins. healing defects by heating a chunk of these data—and you compute an image, The field of synaptic neurotransmis- metal and letting it cool slowly; the at- you still won’t notice much of a differ- sion beckoned because not much was oms settle into the structure with the ence. If you do it randomly, it’s like sort yet known about the atomic-level struc- lowest energy). of low level noise. So, you can take this ture of molecules involved in sending ‘‘I had heard about the general con- set aside and use it only for validation, nerve impulses across synapses or how cept of simulated annealing as an opti- but not to refine the structure.’’ structure could influence the mecha- mization tool from a paper published in Brunger incorporated each new tool nisms. Brunger attended a lecture by Science by Kirkpatrick, Gelatt, and Vec- that he developed, including simulated Reinhard Jahn on neuroproteins. ‘‘I chi in 1983. But they used a Monte annealing and cross-validation, into a talked with him,’’ Brunger says, ‘‘and he Carlo method that would have been growing program he named X-PLOR really got excited about the possibility of very inefficient for macromolecules. My and its successor CNS (which stands for obtaining structures. We were a bit na- approach to simulated annealing was ‘‘crystallography and NMR system’’). He ¨veı because there were quite a few other based on molecular dynamics,’’ Brunger presented CNS to the structural biology large laboratories who were trying to says, ‘‘and shakes up the structure, met- community in a 1998 paper (4). The crystallize the same proteins, and we aphorically, by heating it up in the com- paper, with more than 10,000 citations, didn’t know that they had been trying puter. Before this, people had been is among the 10 most-cited of the de- for some time already.’’ using a method that essentially just went cade in the field of chemistry. ‘‘We have Brunger and his collaborators were downhill. It really made a major impact, many thousands of users of the program able to succeed where others had not because before it took many months to still,’’ he says. ‘‘Eventually CNS became because they had a big toolkit and knew refine a structure.