Developer Tales

Aye Aye Captain

Alexandre Bonvin

Utrecht University

Published April 29, 2019

First, let’s clear the air about one thing: HADDOCK, a popular tool to model interactions between biomolecules, is not named after a saltwater cod.

“It’s not about the fish,” says Alexandre M. J. J. Bonvin.

Bonvin’s structural bioinformatics group is embedded in the Bijvoet Center and part of the nuclear magnetic resonance (NMR) spectroscopy group at Utrecht University, the Netherlands. Officially, HADDOCK stands for High Ambiguity Driven protein-protein Docking. But the NMR naming tradition demands certain creativity.

HADDOCK is the Bonvin group’s flagship software tool..

The inspiration for HADDOCK comes from a ...

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Frame by frame

Nikolaus Grigorieff

HHMI’s Janelia Research Campus

Published January 28, 2019

Rejection is an unavoidable part of science, whether it’s funding for research or manuscripts submitted for publication. But few people showcase their setbacks like Nikolaus “Niko” Grigorieff, whose lab web site features a separate “rejection” section.

As a methods developer in structural biology, Grigorieff may be best known for pioneering a technique known as motion correction in cryo-electron microscopy (cryo-EM). But the numbers tell a different story.

All together, his papers have been cited about 9,500 times, excluding self-citations. Compare that to the 45,000 downloads of rejection letters his web site logged as ...

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Rely on This

Sjors Scheres

Medical Research Council Laboratory of Molecular Biology

Published October 26, 2018

But for the luck of a graduate school admission lottery, Sjors Scheres might have followed in his dad’s steps and become a veterinarian. Instead, he headed in a different direction, creating a new generation of software whose importance in biology was footnoted by the Nobel Prize committee in its scientific explainer for the 2017 winners in cryo-electron microscopy (EM).

In The Netherlands, where Scheres grew up, the only veterinary program was oversubscribed. On a whim, Scheres instead chose chemistry and surprised himself by enjoying it. He discovered a fascination with protein structures and soon zeroed ...

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Mathematically Minded

James Holton

University of California, Berkeley

Published April 28, 2017

James Holton first got interested in structural biology in the late 1980s at a biochemistry summer camp as a high school sophomore. He was flipping through the textbooks and ran into the protein folding problem. “Anyone with a mathematical mind will see this problem and think there’s got to be an easier solution,” says Holton, the Beamline Scientist at the Advanced Light Source at the Lawrence Berkeley National Laboratory.

Holton followed this interest through college and graduate school. He studied biology, but his mathematical bent led him to a career in structural biology writing software ...

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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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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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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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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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U-Store-It

The SBGrid Data Bank 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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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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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. Photo by Christopher ...}

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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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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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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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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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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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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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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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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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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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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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Fahrvergnügen

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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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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Structures Solved Simply

Paul Adams and Tom Terwilliger on 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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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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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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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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