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Schrödinger makes science fun for structural biologists

Published June 17, 2011

Schrödinger, a little like a German car, has good looks and power under the hood. The 3D exterior is powered by Maestro, the primary molecular visualization interface in the Schrödinger Suite that integrates all of the other computational tools. It even supports 3D monitors and glasses that embed the user in a 3D viewing experience.

Overkill? Not so, says Woody Sherman, VP of application science at Schrödinger. Aha moments come when scientists view structures in these 3D renderings. “The most important moments come from combining graphics with calculations,” he says. “We gain intuition from looking at ...

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The Raw and the Cooked

Graeme Winter

Diamond Light Source, UK

Published January 24, 2014

Graeme Winter, author of the xia2 x-ray crystallography data processing software, got his start programming during a stint as an astrophysics graduate student working on software to simulate galaxies. He left astrophysics behind, leveraging his newly minted programming skills to land himself a job as a programmer in crystallography at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, UK.

Crystallography stuck. It wasn't the programming that hooked him, but the mathematics. "Each step in the crystallographic process involves several different areas of mathematics, so I quite enjoyed that aspect of it," says ...

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Creative Copy Cat

Pamela Bjorkman

California Institute of Technology

Published April 25, 2012

For several years now, the lab of structural biologist Pamela Bjorkman, Max Delbrück Professor of Biology at California Institute of Technology, has been trying to find a new way to stop HIV with antibodies that prevent the virus from infecting a cell.

Normally, the body forms antibodies on its own. But in the case of HIV, which mutates rapidly and has few handholds for antibodies to grab onto, scientists have had trouble uncovering natural antibodies. Only recently have the numbers of natural neutralizing HIV antibodies been significant enough to enable researchers to compare them with one ...

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Springsteen, Tolkein, Protein

Alwyn Jones and Frodo

Uppsala University, Sweden

Published June 17, 2011

An unexpected side-effect of Alywn Jones's decision to write Frodo, one of the first computer graphics programs written for Xray crystallography, was learning to swear in German. His teacher? Johann Deisenhoffer, the 1988 winner of the Nobel Prize in Chemistry.

“He was always using my experimental versions,” said Jones, then at the Max Planck Institute for Biochemistry, now professor of structural biology at Uppsala University in Sweden. “He used to swear at me when my program exploded, which it often did.” Back then, in 1976, Jones had happened into computer graphics. “I took a wrong ...

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Membrane Master

Tamir Gonen

HHMI Janelia Farm

Published June 30, 2014

In college at the University of Auckland in New Zealand in the early 1990s, Tamir Gonen’s business classes bored him so much that he had his sister enroll him for his future classes. She put him on her track – medicine – and he never looked back.

Gonen, now a Group Leader at the at Howard Hughes Medical Institute’s Janelia Research Campus, completed his bachelor’s degree in inorganic chemistry and biochemistry with First Class Honors. He focused his research on the lens of the eye, a clear tissue nourished not by blood vessels but by ...

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All Who Wander Are Not Lost

Frank Delaglio

Agilent Technologies

Published February 24, 2014

Frank Delaglio knew he wanted a career in biomedical research at age 7, in 1968, when he saw his baby brother in an incubator being prepared for open heart surgery. Today, he is one of the go-to software experts in nuclear magnetic resonance (NMR), having designed or contributed significantly to the field's key software tools, such as NMRPipe and TALOS. But the path he took to get to this point — and to the point of having a direct impact on biomedicine — was circuitous and long, driven in equal parts by luck and preparation.

Delaglio landed ...

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Pushing the Boundaries

Stephen Harrison

Harvard Medical School

Published April 22, 2013

In the mid-1960s when Stephen Harrison began to determine the structure of the tomato bushy stunt virus, SBGrid didn't exist. There was no need for it. They didn't even have a hard disk for storage.

"Near the end of the 60s they got a disk. That was a big deal," recalls Harrison, Giovanni Armenise-Harvard Professor of Basic Medical Sciences at Harvard Medical School. "One disk."

Lacking storage and a network, as a doctoral student in biophysics at Harvard, Harrison had to walk to the Computer Center to code his programs on punch cards. The ...

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Towards Personalized Oncology

Mark Lemmon

University of Pennsylvania (now at Yale School of Medicine)

Published July 16, 2013

Mark Lemmon's career in structural biology began with a decision not to pursue structural biology. At Oxford University as an undergraduate, he'd been drawn to understanding biochemistry at a structural level. But the thing he wanted to understand most, transmembrane signaling, posed a problem. "In the late 1980s, solving crystal structures of membrane proteins wasn't something one could expect to do," says Lemmon, George W. Raiziss Professor of Biochemistry and Biophysics at the University of Pennsylvania.

So he decided to study membrane signaling using molecular instead of structural techniques. His graduate work at ...

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Share the Wealth

Zbyszek Otwinowski

University of Texas Southwestern

Published August 22, 2012

When Zbyszek Otwinowski, who joined SBGrid in the Spring of 2012 along with 8 other laboratories at the University of Texas Southwestern, came from his native Poland to the United states 31 years ago, structural biology was not on his radar. He had come to the University of Chicago to study physics.

But just two years later, he met the late Paul Sigler, a pioneer in crystallography, who worked on the structure of RNA and regulatory complexes. After that, Otwinowski's path shifted away from physics and towards biology. Otwinowski, now a professor of biochemistry at ...

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Vacc-elerator

Peter Kwong

Vaccine Research Center, NIH

Published December 17, 2013

Peter Kwong was putting the finishing touches on his work at the University of Chicago solving the structure of ?-bungarotoxin, a neurotoxin in snake venom, when structural biologist Wayne A. Hendrickson called from Columbia University. "Would you be interested in working on CD4?" he asked.

The year was 1987. Kwong, who was doing graduate research in the lab of the late Paul B. Sigler, a pioneer in structural biology, was in the process of moving to Yale.

At the time, CD4, the receptor for the human immunodeficiency virus, was so new that Kwong hadn't even ...

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Gone Viral

Olve Peersen

Colorado State University

Published March 20, 2014

After studying membrane proteins in an NMR lab as an undergraduate at Carnegie Mellon University, Olve Peersen went to Yale for graduate school. The year was 1988, the heyday of crystallography at Yale, yet Peersen, for the most part, steered clear of it. "I was focused on membrane proteins and NMR, and perhaps a bit brainwashed," he says.

But the brainwashing didn't last. In fact, Peersen, who is now professor of biochemistry and molecular biology at Colorado State University, eventually found crystallography and uses it and several other tools (though not NMR) in his lab ...

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Inside the Box

Mishtu Dey

University of Iowa

Published September 17, 2013

They say the shoes make the man. For Mishtu Dey, assistant professor of chemistry at the University of Iowa, the shoes made the science.

In 2007, during the last year of her postdoc at the University of Michigan, Dey told her mentor, Steve Ragsdale, that she wanted to crystallize the enzyme she was studying, methyl-coenzyme M reductase (mcr), the only enzyme found in nature that produces methane. Ragsdale, who isn't a crystallographer, gave her the go ahead. "He didn't think I'd actually do it," she says.

The trouble was that oxygen inactivates mcr ...

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Strength in Numbers

Joseph Ho

Academia Sinica, Taiwan

Published March 18, 2013

In graduate school at Boston University, Meng-Chiao (Joseph) Ho nearly quit science. He had chosen to focus on a difficult problem, solving a perfectly twinned protein crystal without a homology model to use for phases. His mentor, Karen Allen, a biochemist and crystallographer, had already spent 12 years trying to solve the structure. After 5 more years and no results worth reporting, Ho had a choice: graduate without a paper to his name or give up.

"I almost became a chef," says Ho, who is now an assistant research fellow at the Institute of Biological Chemistry ...

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The Fixer

Jane Richardson

Duke University

Published October 28, 2013

In the late 1960s, only a dozen or so proteins had been solved using x-ray crystallography. Jane Richardson and her husband, David, solved one of them (Staphylococcal nuclease), while working at MIT and a second of the first 20 (superoxide dismutase) at Duke University, where they still work today. The problem was, even with the solutions in hand, no one could quite comprehend all the complex information in such structures. There was no standard way of visualizing them.

So Richardson, now a James B. Duke professor of biochemistry at Duke University, spent two years teasing out ...

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The Lure of the Sandbox

Paul Emsley and Coot

MRC Laboratory of Molecular Biology, UK

Published October 15, 2011

A little over a decade ago, Paul Emsley, biochemistry professor at the University of Oxford, was looking to ditch his white coat. What he really wanted was to spend more time programming in the computer lab. “I was happy using existing software tools,” said Emsley, who had used O and other tools in his research. “But you go down the pub and think, if only the tool did this, and if only it did that. That festered for years.”

In the late 1990s, Emsley had the opportunity to join the lab of Kevin Cowtan at University ...

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Brush with Fame

Yizhi Jane Tao

Rice University

Published June 14, 2013

In 2006, Yizhi Jane Tao accepted an award for being one of the most influential Chinese at her undergraduate alma mater, Peking University. Other awardees included Oscar-winning director Ang Lee and actress Zhang Ziyi, who starred in Crouching Tiger, Hidden Dragon.

"It was good to see that our work is appreciated," says Tao, associate professor in biochemistry and cell biology at Rice University. "But it made me realize that fame is not important to me. I like my work better."

Tao studies viruses, specifically RNA viruses. She got her start working with bacteriophages in graduate school ...

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Sensing a Change

Brian Crane

Cornell University

Published August 16, 2013

Brian Crane was all set to stay in Canada to attend graduate school when he heard about a new program at the Scripps Research Institute billed as graduate studies "at the interface of chemistry and biology." In 1990, such integrated programs were just emerging, so Crane, a chemist with biochemistry leanings, was intrigued. He had never heard of Scripps, being himself from Manitoba, in Winnipeg, but after a visit to the California campus, he decided the program was a perfect fit.

"The emphasis was chemical, but it had a biology culture," he says. "More freeform and ...

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Sharper Image

Pawel Penczek and SPARX

University of Texas, Houston Medical School

Published June 4, 2012

When Pawel Penczek took his first job in the lab of Joachim Frank, a pioneer in cryo-Electron Microscopy, he had never heard about the technique. "My interest was in digital signal processing," says Penczek, now director of the Structural Biology Imaging Center at the University of Texas - Houston Medical School and lead developer of SPARX, a Cryo-EM image processing software tool. "I was only remotely aware of using EM for biological applications."

When he arrived in Frank's lab in 1989, he became part of the team working on the first cryo-EM construction of the ribosome ...

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X-PLORer

Axel Brunger

Stanford University

Published October 1, 2012

Axel Brunger joined SBGrid in the early days, in 2006, but he may be best known among structural biologists as the man behind CNS (the Crystallography & NMR System), which he contributes to SBGrid, among other tools. Today, however, Brunger focuses almost all of his work on understanding the molecular mechanism that causes neurons to release neurotransmitters and propagate nerve signals.

"Most drugs for treating neurological diseases affect postsynaptic signaling," says Brunger. "If we could develop compounds that could act on the actual release, that could open up a range of more specific and finely tuned ...

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Structures Solved Simply

Paul Adams and Phenix

Lawrence Berkeley Laboratory

Published June 2, 2011

It used to be that to book a trip you'd first need to call every airline to compare flights. Then you'd need to find good hotel deals. Then you'd have to revisit the flights. And so on. The same trial and error approach also used to hold true for structural biology. Frequent failures made scientists all too familiar with square one.

Now, however, what Orbitz and Expedia have done for travel, Phenix has done for structural biology.

Phenix helps investigators solve Xray crystal structures using multiple approaches, including molecular replacement and experimental phasing ...

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Surprise, Surprise

Catherine Drennan

Massachusetts Institute of Technology

Published April 26, 2014

After studying chemistry at Vassar College, Catherine Drennan took a leap from her native New York to a Quaker-run farm school in Iowa. Being the high school’s only science teacher, she taught physics, chemistry, and biology, which included monitoring pregnant hogs and assisting them through labor. "I call it real biology," she says. "At one time, I could tell you all of the signs that a hog was going into labor."

For chemistry, however, that sense of real — the ways in which chemistry could solve problems in the world — wasn’t clear. So Drennan decided ...

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From Curiosity to Cure

Marc Kvansakul

La Trobe University, Australia

Published December 13, 2011

Marc Kvansakul decided to become a structural biologist as a young teen after watching a documentary that described proteins as assemblies of Lego-like blocks. Today Kvansakul’s newly formed lab in the department of biochemistry at La Trobe University in Victoria, Australia, is using what he has learned about the sequences and structures of anti-apoptotic viral proteins to start developing new treatments for Burkitt lymphoma, a form of the disease known to be caused by the Epstein-Barr virus.

Not exactly the same as building yellow and red plastic-brick scale models, but, says Kvansakul, “it’s all ...

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Structural Storyteller

Karin Reinisch

Yale University

Published November 15, 2013

Karin Reinisch had being doing structural biology since graduate school, and as a post-doc solved the reovirus core in the lab of Stephen Harrison. But it wasn't until she arrived at Yale in 2001 to set up her own lab that she found her niche. "At least half of the department, six or seven people at the time, were working in one particular area, how you move materials between different organelles," she says. "That made it a very rich environment for a structural biologist."

Even today, Reinisch, now associate professor of cell biology at the ...

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Playing the Odds

Randy Read and Phaser

University of Cambridge, UK

Published May 19, 2011

Beta-lactamase disarms penicillin, breaking it down before it can do its antibacterial work. But the beta-lactamase inhibitor protein, BLIP, interferes, paving the way for penicillin to do its work.

Exactly how is no longer a mystery. The complex of beta-lactamase and BLIP was solved, painfully, long ago. “It took Natalie Strynadka”—now at the University of British Columbia—“a couple of years to solve,” says Randy Read, professor of hematology at the University of Cambridge and lead developer of Phaser, a structural biology software tool. “Today it's something that can be solved by one of ...

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Unplanned Pioneer

Tim Stevens

Babraham Institute

Published January 15, 2013

When Tim Stevens finished his PhD in biochemistry at the University of Cambridge in 1999, he needed a job to tide him over for a few months. When he discovered that his department had 9 months of grant funding for someone to do Nuclear Magnetic Resonance Imaging (NMR) analysis, he applied.

Even though he'd never done NMR work before, he got the job, and so defined the next decade of his career.

During that 9-month stint, Stevens solved one structure on his own and assisted with another. "I'd done a lot of computing work ...

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Better, Faster, Stronger, More

Victor Lamzin and ARP/wARP

Molecular Biology Laboratory, Germany

Published May 17, 2011

It took Victor Lamzin nearly a year to solve his first structure, an 800-residue enzyme formate dehydrogenase. Later, as a post-doc, he asked his supervisor to let him re-solve it, but this time in just 2 months.

Lamzin, now a group leader and the Deputy Head of the Hamburg Unit of the European Molecular Biology Laboratory, did it. “That's when I realized things could be done even quicker than that. I realized that much of the experience I had garnered and what I'd deciphered from reading the literature and talking to colleagues could be ...

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One Lab, Many Methods

Wesley Sundquist

University of Utah

Published February 12, 2013

Wes Sundquist got his first taste of structural biology as a doctoral student in chemistry at MIT in Cambridge, MA, designing small molecules to bind to DNA and using nuclear magnetic resonance imaging and crystallography to look at them.

"The more I looked at the molecular biology, the more the biomolecules interested me," says Sundquist, professor of biochemistry at the University of Utah. When Sundquist completed his degree in 1988, he swapped one Cambridge for another, spending the following 4 years as a post-doctoral fellow at the Medical Research Council Laboratory of Microbiology at Cambridge University ...

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Escape from the Darkroom

Wolfgang Kabsch and XDS

Max Planck Institute for Medical Research

Published May 19, 2011

As Wolfgang Kabsch headed for the darkroom, facing another day of developing films of Xray diffraction patterns, he passed by a new machine sitting on a bench, unused. It was the mid-1980s and the machine was an early electronic Xray detector, full of new technology but lacking the software to make it usable.

“It was just sitting there, looking at me,” says Kabsch, staff scientist emeritus in biophysics at the Max Planck Institute for Medical Research. “I decided rather than wasting my time in the darkroom, I could program the detector to do something useful.”

Kabsch ...

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Toxic Avenger

Borden Lacy

Vanderbilt University

Published May 21, 2013

While the bacterial toxin that causes anthrax has been used as a deadly biological weapon, from a scientific point of view, it has an upside. "The nice thing about anthrax is that separate proteins make up the toxin," says Borden Lacy. "So long as you keep them apart, it's entirely safe."

If there are nice things to say about other bacterial toxins, she will likely know them. They are her specialty.

Lacy, an associate professor of Microbiology at Vanderbilt University, began her studies of toxins in graduate school at the University of California, Berkeley by ...

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New Kid on the Block

James Chen

Oregon Health and Science University

Published July 29, 2014

James Chen was raised by mathematicians who taught him at an early age to program computers and to think analytically. “Everything had to be formulated. Instead of speaking in natural language, we sometimes spoke in formulae at home,” Chen says with a laugh. No surprise, then, that Chen, assistant professor of biochemistry and molecular biology at the Oregon Health and Science University (OHSU), became an expert in electron microscopy data analysis.

Physics appealed to him as a college student in China, but as a graduate student at Florida State University, he found himself lured into biophysics ...

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Unraveling RNA

Anna Pyle

Yale University

Published July 18, 2012

As a child growing up near Sandia National Laboratory in New Mexico, surrounded by physicists and chemists, Anna Pyle had an unconventional sort of chemistry set. Among her playthings was a cube of depleted uranium (only "slightly radioactive," she says). With the language of science as much a part of her life as English, Pyle, now William Edward Gilbert Professor of Molecular, Cellular and Developmental Biology and Professor of Chemistry at Yale University, chose to study chemistry as an undergraduate.

It wasn't until graduate school at Columbia University that biology grabbed her attention. She began ...

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From Actin to Action

Emil Pai

University of Toronto, Canada

Published January 11, 2013

Emil Pai trained as a classical chemist in the mid-1970s at the University of Heidelberg. He spent his time learning messy, inefficiently named chemical reactions. "A 60 percent yield was cause for celebration," he says.

Then he attended a lecture on enzyme catalysis, a way to perform very precise biochemical reactions. "For a chemist, it was a humbling experience," says Pai. "I realized that to understand these reactions, you have to know what the molecules look like." Pai, now a professor of biochemistry, medical biophysics and molecular genetics at the University of Toronto (and also former ...

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Charm and Diplomacy

Gerard Kleywegt

EMBL-European Bioinformatics Institute, UK

Published March 7, 2012

“I was an angry young man,” says Gerard Kleywegt of his early days in the 1990s as a structural biologist. He’d found his way from the University of Utrecht, in the Netherlands, where he’d done his PhD on Nuclear Magnetic Resonance (NMR) spectroscopy, to Uppsala, in Sweden, where as a young post-doc he was learning X-ray crystallography from Alwyn Jones. “I thought quality and validation of structures was so important that, when I found an error, I was almost shocked.” And he wasn’t quiet about it.

Kleywegt now laughs at his “zeal,” and ...

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Side-Track to Success

Ning Zheng

University of Washington

Published May 13, 2011

When Ning Zheng got side-tracked from his studies of protein degradation, he never expected to end up in the plant world. Today, Zheng, associate professor of pharmacology at the University of Washington and an HHMI investigator, runs a triplicate of research agendas, all rooted in Xray Crystallography, and all aiming to find new therapeutic drugs for human diseases.

Zheng started his career solving large protein-protein complexes of ubiquitin ligases and the proteins they bind with to degrade them. Malfunctions in this process of ubiquitination are involved in several diseases including cancers, neurological disorders and viral infections ...

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Andrew Morin, Ph.D.

Policy Research Fellow

Published August 11, 2014

Just Above the Trenches
Since 2011, Andrew Morin has been a post-doctoral fellow at SBGrid working on “low-level science policy” related to research computing. In contrast to high-level policy, those issues discussed at the National Institutes of Health or in Congress, Morin focuses on issues much closer to the bench, such as how to publish source code, how to license it, and how to share computational results. The work is central to SBGrid’s mission to support and promote the development of scientific software applications used in structural biology and fills a much needed, yet somewhat ...

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Elizabeth Dougherty

Science Writer

Published August 13, 2014

Telling True Tales
Many writers land in their profession by deftly avoiding math and science in school. Not so with Elizabeth Dougherty, who composes monthly profiles of SBGrid members, developers, and applications. Dougherty credits her math degree and computer science experience with providing an unexpectedly useful foundation.

“They’re my favorite interviews of all my work,” says Dougherty, a freelance science writer and editor, about her SBGrid assignments. Since 2011, when the new website featuring SBGrid Tales was introduced, Dougherty has been calling scientists and software developers to hear their stories.

“I ask them to go ...

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Jason Key, Ph.D.

Technical Project Leader

Published August 8, 2014

Master of Many
Jason Key happened upon an ad for a job at SBGrid while browsing a CCP4 bulletin board. He was over 4 years into his second post-doc, at University of Texas Southwestern using NMR to study mammalian oxygen sensing proteins. His previous post-doc had been in Amsterdam at an ultra fast laser lab studying photoreceptors. And before that, he’d been a graduate student at the University of Chicago doing x-ray crystallography.

In other words, he’d just about done it all, which is exactly what the job called for. “I have this broad ...

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U-Store-It

SBGrid’s Structural Biology Data Grid provides an affordable and sustainable way to preserve and share structural biology data

Published March 28, 2016

Evidence of the Higgs boson appears as a bump on a histogram resulting from the analysis of data from millions of detectors at the Large Hadron Collider. What if all that raw data vanished, leaving nothing but the histogram? The physics community would reel.

Yet in structural biology, raw data frequently goes missing. Scientists dutifully store models of proteins in the Protein Data Bank, but the X-ray diffraction data used to derive those macromolecular structures isn’t accessible easily, if at all. One reason is that, until recently, there was no clear place to put it ...

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An Affinity for Affinity…and Corals

John C. Williams

City of Hope

Published August 29, 2014

As a post-doc at Columbia University, John Williams and his wife-to-be wanted a pet. They ended up with the unlikeliest of companions. "We started a reef tank," says Williams.

Williams, now an associate professor of molecular medicine at City of Hope, noticed that all of his corals closed up when he cut one for propagation, a sign that the corals were releasing powerful chemicals. Having trained as a chemist, he recognized the potential for therapeutic leads in his aquarium, but his actual career — that of becoming a crystallographer with a yen for curing cancer — got in ...

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In Search of…New Drugs

Doug Daniels

Broad Institute

Published September 30, 2014

When Doug Daniels finished his chemistry degree at the University of Michigan and set off for The Scripps Research Institute for graduate study, he’d already made a key career decision. "I decided I was more interested in the discovery and development of drugs than in the practice of prescribing them," he says.

Having ruled out medicine or even an MD/PhD program as a way forward, he instead dove into structural biology. He’d come to love organic chemistry in college, but it was the visual aspects of how structure relates to reactivity that hooked ...

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Carol Herre

Software Release Engineer

Published August 15, 2014

Your Software is Served
Carol Herre joined SBGrid in early 2014, joining the internal staff at Harvard Medical School as a release engineer. She has taken on the challenge of applying the SBGrid model to other fields, such as genomics, and is spending her time finding, compiling and testing new software.

“We’re trying to provide the biological scientific community with software to do their jobs,” she says. “The existing model works really well for structural biology, so we’re trying to extend that to other biological sciences.”

Herre is working with the Tools-and-Technology Committee at ...

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Crystallography for Kids

Lynne Howell

The Hospital for Sick Kids, University of Toronto, Canada

Published May 17, 2011

Most people, armed with tartar-control toothpaste and a miniature scrub-brush, do battle with biofilms every morning. Biofilms form when bacteria attach to a surface, like a tooth, and form a colony encased in a protective coating.

SBGrid member Lynne Howell, senior scientist at The Hospital for Sick Children (SickKids) and a biochemistry professor at the University of Toronto, studies biofilms formed by Pseudomona aeruginosa, a bacterium that afflicts Cystic Fibrosis (CF) patients by forming biofilms inside their lungs. She recently uncovered the structure of AlgK, an outer-membrane lipoprotein on P. aeruginosa that helps the bacteria form ...

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Bloodletting and Other Studies

Pedro José Barbosa Pereira

Institute for Molecular and Cell Biology, Portugal

Published November 25, 2014

When searching for a graduate program, Pedro José Barbosa Pereira was drawn to the lab of Nobel Laureate Robert Huber at the Max Planck Institute of Biochemistry in Munich for obvious reasons. But it was the leeches that made him stay.

The laboratory was beginning to explore anticoagulation factors that allow creatures like leeches and ticks to survive. “Leeches can feed twice a year and keep the meal liquid in their guts for six months. This is absolutely incredible,” says Pereira. “How do they do it?”

Pereira later ended up on a different project, but that ...

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Basics and Beyond

Qing Fan

Columbia University

Published December 18, 2014

As a chemistry graduate student at Harvard University, Qing Fan made the rounds of laboratory open houses. She stopped after she saw a short talk by the late Don Wiley about how major histocompatibility complex (MHC) molecules are able to recognize and differentiate a large range of antigens. “It is a very elegant mechanism, and I was fascinated,” says Fan, assistant professor of pharmacology and pathology and cell biology at Columbia University.

She joined Wiley’s lab immediately. “Don Wiley pioneered the use of structural biology and structural methods to provide insights into biological problems,” she ...

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Keep on Moving

James Berger

Johns Hopkins School of Medicine

Published August 23, 2015

Say I’ve got two related motor proteins, says James Berger, professor of biophysics and biophysical chemistry at the Johns Hopkins School of Medicine, both helicases. One, which is responsible for DNA replication, moves at high speeds, up to 1000 base pairs per second. The other, involved in transcription, plods along at 30 bases per second. These proteins share a common ancestor, but have very different physical behaviors. “Why?” he asks. “What is it in the structure that encodes that maximum speed limit at which the motor can move? I would argue that you can look ...

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Cut and Paste

Martin Jinek

University of Zurich

Published January 28, 2015

In January 2013, Martin Jinek published a paper in eLife showing that the CRISPR endonuclease Cas9, molecular scissors that silence the DNA of invading viruses in bacteria, could also be used to edit the DNA in human cells. The work coincided with similar findings from George Church at Harvard Medical School and others, and helped launch the CRISPR gene editing revolution.

The key discovery, however, had come a few months earlier, the result of basic scientific curiosity. Jinek, then a postdoc in the lab of Jennifer Doudna at the University of California at Berkeley, had become ...

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Not a Structural Biologist

Enrico Di Cera

Saint Louis University

Published December 17, 2015

Enrico Di Cera studies proteins involved in blood coagulation. He has spent a significant portion of his career working out the function and structure of thrombin, and has recently solved the first structure of prothrombin, thrombin’s precursor in the body.


Conformational plasticity of prothrombin. The three structures are aligned over the rigid kringle-2/protease pair and then visualized separately in the same orientation. Individual domains are labeled and colored as follows: Gla domain (Gla, blue), kringle-1 (K1, red), kringle-2 (K2, green), A chain (Ac, orange), B chain (Bc, yellow). The flexibility of Lnk2 causes the ...

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Trans-Plant

Gang Dong

Max F. Perutz Laboratories at the Medical University of Vienna

Published September 26, 2015

After finishing his postdoctoral research at the Yale School of Medicine in 2008, Gang Dong moved his family to Vienna, Austria, to start his own research group at the newly established Max F. Perutz Laboratories (MFPL) at the University of Vienna and the Medical University of Vienna. He had no apartment and didn’t speak German, and the relative who had been helping them with their three-month-old daughter had moved back to China. “The first few months were very hard for me and my family,” says Dong, Junior Group Leader at MFPL.

Since then, Dong has ...

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Big Questions, Big Answers

Jennifer Doudna

University of California, Berkeley

Published February 22, 2016

Jennifer Doudna has reached celebrity status as one the inventors of the CRISPR/Cas9 genome editing technology. The tools, the equivalent of a toolkit for performing precision surgery on the DNA of any organism, have revolutionized research in the biological sciences and could do the same for medicine in the near future. It is work related to CRISPR that intrigues her most right now, but not so much in terms of directly advancing the tools. Rather, Doudna is — and has always been — interested in the fundamentals.

“Fundamental research is critical for everything we do,” says Doudna ...

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Intron Intrigue

Navtej Toor

University of California at San Diego

Published February 20, 2015

When Navtej Toor started searching for a post-doc in 2004, he applied to just one lab, that of Anna Pyle at Yale University. It was a long distance from the University of Calgary, where he’d done his undergraduate and graduate studies in biochemistry, and a far cry from his nearby rural hometown of Sparwood, British Columbia. But Pyle’s interests most closely resembled his own.

Toor, now an assistant professor of chemistry and biochemistry at the University of California, San Diego, had become interested in RNA as an undergrad. Later, when he saw the high-resolution ...

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Picture This

Georgios Skiniotis

University of Michigan Life Sciences Institute

Published March 20, 2015

When Georgios Skiniotis arrived at the University of Michigan Life Sciences Institute in 2008, his first task as a new professor was to build a cryo-electron microscopy lab. Since then, he’s made good use of it. His work has contributed to Nobel Prize-winning research, and in his own lab, he uncovered the inner workings of polyketide synthases, natural enzymes that act as factories to assemble complex chemicals that have antibiotic and anticancer properties. “We’re planning on using this knowledge to redesign these machines to create new novel molecules that might have pharmaceutical applications,” says ...

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Piotr Sliz, Ph.D.

Principal Investigator, SBGrid

Published August 1, 2014

The Natural Bridge
In 2013, Piotr Sliz and the team at SBGrid published a paper in eLife describing, for the first time in a formal, academic fashion, the SBGrid model. In existence since 2000, SBGrid now has a life of its own, with 250 members and several employees supporting its operations. “We have an excellent team in place,” says Sliz, SBGrid’s founder and director. “It’s almost self-propelling.”

But turning SBGrid into an international consortium hasn’t been Sliz’s only focus. During these past ten-plus years, he has advanced computing at HMS, expanded SBGrid ...

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The Natural Bridge

Piotr Sliz

Harvard Medical School

Published June 13, 2014

In 2013, Piotr Sliz and the team at SBGrid published a paper in eLife describing, for the first time in a formal, academic fashion, the SBGrid model. In existence since 2000, SBGrid now has a life of its own, with 250 members and several employees supporting its operations. “We have an excellent team in place,” says Sliz, SBGrid’s founder and director. “It’s almost self-propelling.”

But turning SBGrid into an international consortium hasn’t been Sliz’s only focus. During these past ten-plus years, he has advanced computing at HMS, expanded SBGrid beyond X-ray crystallography ...

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Two Labs, Many Methods

Michael Sattler

Technical University Munich, Helmholtz Zentrum München

Published April 28, 2015

Two Labs, Many Methods Michael Sattler / Technical University Munich, Helmholtz Zentrum München

In 2011, Michael Sattler took a look at an RNA binding protein that was known, based on earlier X-ray crystallography work, to have a structure with a specific arrangement of two RNA binding domains bound to its RNA ligand. Using nuclear magnetic resonance (NMR) spectroscopy, however, he found at least two different arrangements of the two domains in the protein: one open, one closed, neither resembling that of the crystal structure. “The crystallography missed that there are closed and open states. It’s something ...

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Divide and Conquer

Kevin Corbett

University of California, San Diego

Published November 19, 2015

Kevin Corbett got his start washing dishes. The job, at TechLab Inc., a small biotech near Virginia Tech, led to research investigating the life cycle of a parasitic amoeba at the University of Virginia, where he was a biochemistry undergraduate.

Later, in the spring of 2000, he walked into the office of the late Don Wiley at Harvard for his first graduate school interview. “He sat me down in front of a Silicon Graphics workstation, gave me a pair of 3D glasses, and for the first time I saw how a protein was built,” says Corbett ...

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From Disorder, Function

Julie Forman-Kay

The Hospital for Sick Children, University of Toronto

Published June 29, 2015

After earning a chemistry degree at MIT in 1985, Julie Forman-Kay headed to Yale for graduate work in the lab of structural biology pioneer Fred Richards. Forman-Kay – who says she never grew out of asking “Why?” – had found an ideal mentor. “He was a wonderful scientist who was more interested in questions than techniques,” she says.

The question that stuck with Forman-Kay concerned protein dynamics and disordered states. Though she was initially interested in protein structures, she later realized that many proteins and protein regions function in the disordered state, so over time, her question evolved ...

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Totally Tubular

Antonina Roll-Mecak

National Institutes of Health

Published July 27, 2015

Antonina Roll-Mecak was an accomplished pianist when she moved to New York from Romania, but she came for the science, specifically to study chemical engineering at Cooper Union. “I loved math and music. Those two things were encouraged in my family,” she says.

Now Roll-Mecak is applying her mathematical mind to cell biology in an effort to crack the tubulin code. Tubulin proteins form hollow tubes inside cells called microtubules that provide cytoskeletal structure and also act as a highway system for cellular traffic. The tubulin code refers to post-translational modifications to tubulin that are thought ...

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Spiro-Gyra

Alejandro Buschiazzo

Institut Pasteur, Montevideo, Uruguay

Published July 27, 2016

When Alejandro Buschiazzo took on the responsibility of building a structural biology core facility in Latin America, he was taking a risk. He was an assistant professor at the Institut Pasteur in Paris, and his career as a structural biologist had only just begun. Plus the institute he was moving to, the Institut Pasteur in Montevideo, Uruguay, was also brand new.

But to Buschiazzo, the risk was worth it. “Structural biology is quite underdeveloped in Latin America, from Mexico down,” he says. “So this was very exciting for me. It was a risk, but it was ...

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Pharm Team

Oleg Tsodikov

University of Kentucky College of Pharmacy

Published August 24, 2016

Heading a small lab of just three people at the University of Kentucky College of Pharmacy, Oleg Tsodikov, the only structural biologist at the College, is juggling multiple drug discovery projects. “It’s a small structural biology community here, but with good facilities,” says Tsodikov, Associate Professor of pharmaceutical sciences at the University of Kentucky (UK).

The project that is farthest along involves the discovery of small molecules for use in combination with drugs of last resort for extensively drug-resistant tuberculosis infections. These small molecules interrupt the pathway that confers resistance to aminoglycoside drugs such as ...

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SBGrid Assumes Ownership of PyMOLWiki

Published September 15, 2016

After ten years of work developing and managing the PyMOLWiki, Jason Vertrees is turning over the helm to SBGrid. “They’re getting the whole site,” he says.

To Vertrees, that site represents more than helpful information and guidance for PyMOL users. It’s a mantle of sorts, a duty he took on to fill a need and kept working on to carry out the original vision of PyMOL as open source software. Open source software benefits from the verification and improvement that comes when code is shared, tested and fixed by a community of developers. It ...

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Here Be Dragons

Brian Fox

University of Wisconsin, Madison

Published September 28, 2016

In recent work, Brian Fox and colleagues at the Great Lakes Bioenergy Research Center at the University of Wisconsin-Madison characterized glycoside hydrolases, enzymes that digest cellulose and can be used to turn plants such as switch grass into biofuels. These enzymes occur in nature with a wide range of diversity. Genomic variations yield over thousands of unique proteins that maintain a similar core function, but with a range of sweet spots for temperature, acidity, and substrate preference.

A key focus of the Center, which collaborates with other labs, including the Joint BioEnergy Institute, Sandia National Laboratories ...

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Escape Artist

Katya Heldwein

Sackler School of Graduate Biomedical Sciences at Tufts University

Published December 19, 2016

Katya Heldwein’s first investigations of herpesviruses focused on how they get into host cells. In the process, she became interested in how these viruses get back out again. Herpesviruses replicate their genomes in the cell’s nucleus and package them in capsids. But these capsids are too large to pass through the nucleus membrane pores. “It wasn’t clear how they were getting out,” says Heldwein, associate professor of molecular biology and microbiology at Tufts.

So in 2016, she solved the structures of two viral proteins involved in the process. The work helped her figure ...

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State of Fusion

Jason McLellan

Geisel School of Medicine, Dartmouth College

Published October 27, 2016

Viruses like human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), and influenza have proteins on their surface that undergo dramatic conformational changes and allow the virus to fuse with a host-cell membrane and infect the cell. Jason McLellan, Assistant Professor of Biochemistry and Cell Biology at the Geisel School of Medicine at Dartmouth College, specializes in understanding these fusion proteins. He applies what he learns to develop new ways to stop the proteins from being triggered to change shape and cause infection.

Early on, McLellan planned on going to medical school, but organic chemistry labs had ...

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Nature’s Confectioner

Jochen Zimmer

University of Virginia

Published November 29, 2016

In early 2016, Jochen Zimmer published a series of structural snapshots of molecular machinery during different stages of assembly and secretion of cellulose across the cell membrane. The series of images reveals a two-part system; one part of the machinery repeatedly adds on to the polysaccharide and another, a helix that acts as a lever, advances it. Zimmer, an associate professor of molecular physiology at the University of Virginia, even engineered a minuscule tether to tie back the lever to verify that this would, indeed, stall the transport process.

The work is part of a collection ...

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Turning the DIALS

Nicholas Sauter

Lawrence Berkeley National Laboratory

Published June 29, 2016

Nicholas Sauter began working on DIALS (Diffraction Integration for Advanced Light Sources) in 2011 because he and his colleagues recognized that the experimental methods of X-ray crystallography were changing, and changing fast. To be usable, the software that automates crystallography experiments must be able to keep up.

So he and his team at Lawrence Berkeley National Laboratory and collaborating teams at CCP4 and at the Diamond Light Source synchrotron in the United Kingdom developed a modular system that allows new algorithms to be dropped in as new experimental methods and technologies emerge. Examples include handling data ...

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Mobilizers

Phoebe Rice

University of Chicago

Published January 31, 2017

A few years ago, at a New Year’s Eve party in her neighborhood, Phoebe Rice mentioned, as you do, that she needed some methicillin-resistant Staphylococcus aureus (MRSA) strains.

A neighbor responded: “Have you met Bob and Susan?”

They had a freezer-full and were willing to share. Soon after, Rice, professor of biochemistry and molecular biophysics at the University of Chicago, began investigating the mobile elements of DNA that give Staph its methicillin-resistance capability.

Initially she focused on the DNA recombinase protein that allows the mobile element, a type of genomic island, to insert itself into ...

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Fixer Upper

Brandt Eichman

Vanderbilt University

Published February 27, 2017

Soon after starting his lab at Vanderbilt University in 2004, Brandt Eichman attended a DNA repair meeting in Bermuda. When the Keynote speaker mentioned two new glycosylases, enzymes that recognize and repair damaged DNA, Eichman scribbled the names in his notebook: AlkC and AlkD.

Back in Nashville, Eichman, who had studied glycosylases as a post-doc, noticed that the genetic sequences of these glycosylases didn’t look like any others he’d seen. His lab found that the structure of AlkD also looked different. “It didn’t look like any other DNA binding protein in the database ...

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Pipeline Dreams

Bridget Carragher and Clint Potter

Simons Electron Microscopy Center at the New York Structural Biology Center

Published April 26, 2016

A year ago, Bridget Carragher and Clint Potter’s group broke the so-called three-angstrom barrier for electron microscopy (EM). Prior to their work, so many structures had been solved using EM at 3.4 or 3.5-angstrom resolution that people had started to believe higher resolutions were out of reach with the technology.

"Our group set out to show that EM could do better,” says Carragher, co-Director of the Simons Electron Microscopy Center (SEMC) at the New York Structural Biology Center (NYSBC). “We did things carefully and in a fully automated fashion and got to 2 ...

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Into Alignment

Geoff Barton

Division of Computational Biology, University of Dundee

Published May 27, 2015

In 1987, when Geoff Barton was a graduate student learning computational structural biology at the University of London, just 6000 protein sequences were known, but their numbers were rising exponentially, and it was becoming clear that they had commonalities. Sequences that yield valuable functions have staying power, so they are conserved throughout evolution. Finding these recurring patterns, however, required painstaking pencil and paper comparisons.

A page from Barton's lab book in around 1988. It shows a multiple sequence alignment produced automatically by his alignment softwstrong textare, printed out then coloured by hand to ...

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Wire Models, Wired

A brief history of UCSF Chimera

Published October 29, 2014

The molecular graphics software called Chimera, written and supported by a team of scientists in Tom Ferrin’s lab at the University of California, San Francisco (UCSF), has been cited over 7000 times and helps biologists and drug developers visualize molecules and biological structures in 3D at various resolutions. The tool has a personal history that traces back to 1994, and an ancestral history that stretches nearly four full decades earlier, to a London lab in 1955 and a man named Robert Langridge, also known as the pioneer of molecular graphics.

Bob Langridge Bob Langridge. Photo by Christopher ...

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Stop, Collaborate and Listen

Eleanor Dodson

York Structural Biology Laboratory, UK

Published November 5, 2012

Back in the mid-1970s, the British government funded several collaborative computing projects. Among them (14 in all) was Collaborative Computing Project 4, known by structural biologists as CCP4. "The idea was that computers were so expensive, you'd probably only have one in London and maybe one in Manchester, so everybody would have to collaborate on using the hardware and developing software," says Eleanor Dodson, Professor Emeritus at the York Structural Biology Laboratory and a contributor to CCP4 from the beginning.

By then, Dodson had already been involved in structural biology for over a decade. With ...

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Computing Cellular Clockworks

Klaus Schulten

University of Illinois, Urbana-Champaign

Published October 23, 2015

Physicist Klaus Schulten once imagined becoming a dancer, relying on nothing but his own mind and body to perform. “But I was not a good dancer,” he says. “So my next thing was theoretical physicist. Just myself, pencil and paper — and in my case, also an eraser.”

That dream was also thwarted. Today, Schulten relies on some of the most powerful and expensive computing equipment on earth to carry out his work, which applies theoretical physics to the understanding of biological systems. His most recent work involved the molecular simulation of an organelle that converts light ...

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Unstructured

A Brief History of CCP4

Published December 12, 2012

Sit down in front of a newly installed copy of CCP4 today, and you will find approximately 250 computer programs for solving protein structures. The list of programs includes several with catchy names, such as beast (for molecular replacement), dimple (for ligand identification in difference maps), crank (for experimental phasing) and buccaneer (for model building), and some cryptic, such as seqwt and npo. Nearly two dozen applications support file manipulations and format conversions. Still more are riders-on, either deprecated or unsupported.

The seeming mishmash is so by design. "CCP4 has always been a very loose collaboration ...

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Garbage Out

Kay Diederichs

University of Konstanz

Published March 30, 2017

In 2011, Kay Diederichs welcomed longtime friend and colleague Andrew Karplus into his lab at the University of Konstanz in Germany. The two had met in the 1980s at the University of Freiburg when Diederichs was a graduate student learning X-ray crystallography.

Over the years, they’d tried to improve the tools structural biologists use to assess X-ray diffraction data quality. Their efforts were respected; a 1997 Nature Structural Biology paper they co-wrote describing a new data quality indicator has been cited around 800 times. Yet few used the new formula. “People stuck with the old ...

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