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Bild Der Wissenschaft 2010, 4, 18-23 PROTEINS >>Life & Environment PERFECTLY STRUCTURED Proteins control the entire life – if they are folded properly. Incorrectly folded proteins are responsible for serious illnesses such as Alzheimer’s and Parkinson’s disease. Researchers are using supercomputers for the ever more accurate prediction of the spatial structure of key molecules. 18 bild der wissenschaft (picture of science) 4/2010 Amino acid chains have a tendency to form into spirals or “beta-pleated sheets” – symbolized with arrows here. However, this is only the secondary structure. How spirals and pleated sheets are winding around each other remains a mystery. IN A NUTSHELL Decoding the three-dimensional structure of proteins is so difficult that researchers have only identified the shape of 0.7 percent of known proteins. Therefore, biologists and computer scientists are using savvy and computers to shed light on more protein structures. They are pitting their strength against each other in N. Speicher/Laguna Design Design N. Speicher/Laguna an international prediction competition. bild der wissenschaft 4/2010 19 PROTEINS Professor Jens Meiler (left) and his ambitious team of PhD students in Nashville (right): in 2008, they entered an international competition with a new self-developed prediction program. by Frederik Jötten IT IS MAY 5, 2008, 02:30 pm in problem. But the three-dimensional stops the process and makes sure that the Nashville, Tennessee when the race structure is only known for 0.7 percent repair system is initiated. If the damages begins. Outside the window, the sun of of macromolecules – and this structure is involving the DNA are severe, it the southern state is scorching the the sole decisive factor for whether they activates the self-destruction of the cell. Vanderbilt University campus. On the can fulfill their function in living However, if p53 is incorrectly folded due inside, in a comfortably air-conditioned creatures. to a mutation, it is no longer able to room full of computers, the competitors monitor the genome. Cells can then wearing jeans and T-shirts are ready to Incorrectly folded proteins cause divide in an uncontrolled way – cancer get started. Nils Wötzel, Julia Köhler, illnesses; this is generally known at least develops. p53 is mutated in 50 percent of Nathan Alexander and Merr Karakas, all since the causes for BSE and the all tumors involving humans. PhD students in their mid-twenties are Creutzfeldt-Jakob disease have been staring at one of the monitors, waiting. identified. The modification of their ROSETTA’S LIMITATIONS Finally, a sequence of letters appears: three-dimensional structure turns Attempts to determine protein structures MFSLRDAKC… An unpronounceable harmless proteins into deadly prions are ongoing around the world, to word composed of 103 letters. It which in turn convert harmless proteins understand the causes of illnesses and to identifies a protein consisting of a chain into the dangerous form. Prion diseases develop new medications. However, 50 with 103 amino acids. This is the starting are rare, but they illustrate the potential percent of all drugs bind to proteins signal of the competition at the end of consequences of structural alterations of integrated in the cell membrane – and for which the young scientists belonging to proteins. Illnesses in which proteins these, it is even more difficult to the group of German structural biologist clump together rather than adopting their determine the three-dimensional shape Jens Meiler are hoping to predict what proper shape are much more common: compared to soluble proteins: the this and more than 100 other proteins the Alzheimer’s and Parkinson’s structure is only known for 0.04 percent. look like. They are joined by 236 other diseases affecting millions of people as competing teams from around the world. they get older are the result of this Jens Meiler’s working group in defective protein folding. Recent studies Nashville is committed to changing this. One of the main challenges of modern suggest that “sick” proteins are refolding The international competition the four biology is to define the structure of traditional shapes of certain proteins PhD students are participating in is proteins. Proteins control all processes of within the body – similar to prions. called “CASP”. The English life – in plants, animals and humans. abbreviation stands for “Critical Whether it relates to the contraction of And then there are the disorders Assessment of Techniques for Protein our muscles, the digestion of food or our triggered by isolated mutations – genetic Structure Prediction”. The procedure is sense of seeing, hearing and tasting, changes resulting in a non-functional as follows: Researchers who defined a proteins mediate almost all processes in protein. Protein p53 is known as the proteins structure experimentally are living creatures – including pathogens. “master watchman of the genome” for its holding off with the publication of their These days, defining the order of the ability to prevent tumors. If errors in the data. The prediction teams are provided amino acids of proteins is no longer a duplication of the genotype occur, it with the letter sequence, the so-called 20 bild der wissenschaft 4/2010 Target 409, a protein from the bacterial cell wall: According to the computer program of Meiler’s team, it could adopt the shapes 1 to 5. Picture 6 illustrates the actual structure in grey along with the details of the best predictions from the Nashville team in color. amino acid sequence, use the Rosetta’s capabilities are limited”, computer programs to create a says Meiler. “Our program is hypothetical structure – and the designed to overcome these models and reality are compared limitations.” weeks later. At a conference held seven months after the start of the CHANNEL IN THE HEART competition, it will be announced HERG is an example of a membrane which teams were most successful. protein; it occurs in cells of the heart muscle and forms a channel between Jens Meiler already participated in the inside and the outside of the cell. CASP as a post doc. He worked for Potassium ions are flowing out of the inventor of the computer-aided the cell through this channel after protein structure prediction tool, the contraction, a requirement for David Baker in Seattle for four the heart to be able to pump blood years. While there, he was involved soon again. If the channel does not in the development of the best work properly, it may result in known and thus far most successful prediction program: “Rosetta”. With Rosetta, Meiler won first place in CASP twice. His working group is now participating with a self- developed program for the first time. “For membrane proteins and proteins not resembling any previously known molecules, PROTEINS arrhythmia. Numerous drugs, Nils Wötzel starts the program only realized a few of these including some antibiotics and designed to predict the structure. The combinations – namely ones that antipsychotic drugs bind to HERG, supercomputer which fills an entire occur in living creatures in stable thus causing arrhythmia. Therefore, room in the neighboring building and three-dimensional shapes: for every potential drug must now be has a capacity comparable to 2000 example in a basic shape and in investigated first to find out whether traditional PCs starts the calculation. deviating variations created by the it binds to HERG before it can be Preliminary models will be available interaction with other molecules. tested in humans. And this is a in a few days. problem: although HERG is one of CENTURY-OLD DREAM Proteins are part of the most complex the most studied proteins, the Proteins fold as early as during molecules overall. They contain up to determination of its exact structure 100,000 atoms and create the most synthesis. In doing so, they are has been impossible to this day. diverse structures – ranging from the driven by inner energies forcing Algorithms, neuronal networks and tear-resistant construction material them into the most favorable supercomputers are currently being collagen to the variable antibody. energetic status. These forces have used to speed up the search. This is how biologists determine the real 3D structure of a protein: they allow crystals to form (left), bombard such a crystal with X-rays in a diffractometer (center) and determine the structure from the diffraction pattern (right). The 8th round of the CASP The structural formulas of the 20 one thing in common: they are competition also includes a protein amino acids from which organisms already present in the amino acid which is involved in the structure of establish proteins are written with sequence. Therefore, researchers bacterial cell walls and plays a key marker on a board hanging on the have been dreaming for centuries to role in the resistance against wall next to the computer. All of predict the structure of a protein antibiotics. Many antibiotics, them have an identical part – and a solely based on the sequence of the including penicillin, bind to this so-called residue which makes them amino acids. But in spite of years of protein, thus inhibiting its function different. intensive research, computer models and preventing the pathogens from are only approximations so far. propagating. However, for the The length of an average protein is Individual atoms within a protein researchers in Nashville, this is 300 amino acids, in other words, have an estimated diameter of one simply “target” number 409. CASP there are 20 to the power of 300 angstrom (1.0 x 10-10 meter). On is not about the function of certain possible combinations. This figure is average, the best estimates are off by proteins, but rather about the basic so large that the number of atoms in up to 5 angstroms, moderate principles of protein folding and the entire universe would not suffice estimates by 10 and poor ones by 20 how they can be computer- to create only a single sample of and more.
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