Warren L. DeLano 21 June 1972–3 November 2009

On 3 November our community lost a young, extremely talented scientist under tragic circumstances when Warren DeLano died suddenly. To the readers of Nature Structural & Molecular Biology and to the larger biochemical and computer science communities, Warren is best known for his computer system PyMOL, an Open Source program for visualization of complex macromolecular systems. Chances are that in this issue, most of the illustrations of biomolecules were created with PyMOL. Warren grew up in Palo Alto, California, at a time and with a loving family that greatly valued the development of computer technology and science. Warren’s life-long commitment to computational biosciences began when he was an undergraduate research student (majoring in molecular biophysics and biochemistry (MB&B) and computer science at Yale University) and asked one of us (A.T.B.) to supervise his MB&B senior thesis research. At the time, MB&B and the Center of Structural Biology had become a powerhouse of what we now know call “ structural biology.” Warren was attracted to solving the complexities of macromolecular systems using computational tools. I (A.T.B.) still remember when Warren showed up in my office one day. He was clearly very special, full of energy, and eager to become involved in computational research in my lab. I first suggested that he work on structure prediction of helical bundles. Then, after graduating, he continued in the lab for two years as “Scientific Programmer,” working on a second project involving molecular replacement. Two first-author papers quickly resulted. But, in my memory, the most remarkable thing happened after a lab discussion about my general idea of creating a universal computing language for X-ray crystallography (what would eventually become the Crystallography and NMR System, CNS). Warren recognized the importance of implementing powerful scripting capabilities for the new system. Within days he had created very complex code in CNS (see subroutines parser.f and define.f), which implemented hierarchical data structures, scope and subroutines, all written in FORTRAN. It is an example of what the Stanford University computer scientist Donald E. Knuth has called (in the title of his best-known work) The Art of Computer Programming (D.E. Knuth, vols 1–4, Addison-Wesley, Reading, Massachusetts, USA, 1968–2005). Essentially, it does not matter what programming language one is using—elegant programs can be written in any language. And yes, Warren’s code is truly elegant. For Warren, programming was not just a job or a means to another goal—it was like playing a musical instrument. The programs he designed were symphonies in computational space: integrated, complex and elegant at the same time. What’s more, these masterpieces can be played by everyone. Before Warren moved on to graduate school at the University of California at San Francisco (UCSF), he had already started to work on what would eventually become PyMOL. Based on a rough idea of “ defining objects and displaying them on a graphics terminal” and a rather clumsy and simple implementation that I had written in the mid-1980s to feed molecular information to a noisy refrigerator-sized Evans & Sutherland vector graphics computer, he took the concept and made it truly useful and accessible to everybody. PyMOL was the first intuitive molecular graphics program for the laptop era with the kind of click-and-drag functionality that we are now all accustomed to. And of course the rest is history: PyMOL has developed into one of the most widely used molecular visualization systems around. The first time I (J.A.W.) met Warren was when he showed up at my office at Genentech. His hands were sweating and he was shaking as he announced that he had to work in my lab as a rotation student in the Biophysics Program at UCSF, where I had an adjunct appointment. Frankly, I was a little reluctant, as I knew he had virtually no wet-lab experience. But I couldn’t resist his intense passion, incredible smarts and no-fear attitude. One of the most amazing things about protein-protein interfaces is their promiscuity—that is, the fact that the same interface can bind multiple partners whose folds can be completely different. Warren’s project was to use peptide-phage display to see whether naive peptides would seek out a well-known promiscuous epitope at the Fc region of antibodies. He selected for peptide binders, optimized them and rigorously characterized them using multiple biophysical methods, including solving the X-ray structure of the peptide bound to the Fc. Remarkably, his peptide, shown by the X-ray structure to be a simple -hairpin, bound exactly over the promiscuous epitope! By comparing the contact properties of four natural Fc-binding ligands to that of his naive peptide, he began to define the minimal binding properties. Importantly, he revealed the highly adaptive nature of these interfaces. To visualize this adaptive property, he began to further develop the software for PyMol in his spare time. In particular he developed a special application he called RigiMol—one of the first molecular movie programs that allows one to morph between static structures. For Warren’s superb thesis, published as a first-author paper in Science entitled “Convergent solutions to binding at a protein-protein interface” (W.L. DeLano, M.H. Ultsch, A.M. de Vos and J.A. Wells, Science 287, 1279–1283, 2000), he was awarded the annual Julius Krevans Award for the best PhD thesis at UCSF. Not bad for a computational geek. Warren was a driven adventurer. About the time he graduated in 1998, I decided to leave Genentech for a start-up company, Sunesis Pharmaceuticals. Warren said he had to join as one of the first founding scientists, and he flew into the opportunity. He was seemingly doing everything, from working at the bench to evaluating novel fragmentbased discovery technologies to setting up our computational group. He even insisted on physically setting up our first IT system, pulling wires to work stations, connecting routers and our company e-mail Axel T. Brunger is at the Howard Hughes Medical Institute and the Departments of Molecular and Cellular Physiology, Neurology and Neurological Sciences, and Photon Science, Stanford University, Stanford, California, USA, and James A. Wells is in the Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California at San Francisco, California, USA. e-mail: brunger @stanford.edu and Jim.Wells@ucsf.edu O B I T UA RY