20 Jan, 2016
Stacking up the proteins. After decades of attempts, scientists finally succeeded in unraveling the TIM-barel protein. Here is a graphic depiction of how their simulations fared against the Astral SCOPe 2.04 database. Courtesy Po-Ssu Huang.
Computational models open up new possibilities for designing proteins for targeted disease treatment. Using the Open Science Grid (OSG), Baker Lab researchers at the University of Washington have simulated a protein that has stymied scientists for the last 25 years, and have opened the way for a new generation of custom-designed enzymes.
The cylindrical TIM-barrel (triosephosphate isomerase-barrel) protein occurs widely in enzymes and is an attractive goal for research. But ever since it was first targeted in a European Molecular Biology Organization workshop on protein design in 1987, modeling this structure has been an elusive goal. Even the shortest TIM-barrel structure is highly complex.
Now, thanks to OSG resources, the Baker Lab has generated large numbers of TIM-barrel structures as starting points for enzyme design calculations. Published in Nature Chemical Biology, their results will aid de novo design of custom-made catalysts or binders without the need to negotiate the structural complexity of naturally occurring proteins.
To scale up simulations for the TIM-barrel computational model, the research team used the OSG, which is supported by the US National Science Foundation and the US Department of Energy’s Office of Science.
“The massive computing power of the OSG allowed us to quickly get answers,” says Po-Ssu Huang, one of the lead researchers on the paper and a research scientist at the Baker Lab. In the past year, the researchers used an average of 46,000 core OSG hours per week — a total of around 2.4 million core hours.
“Baker Lab has its own local HTCondor submit host that is connected to the OSG virtual organization HTCondor infrastructure,” says Mats Rynge, a computer scientist at the Information Sciences Institute of the University of Southern California and a member of the OSG User Support team. “Jobs submitted on the host are automatically scheduled onto available resources across the OSG.”
Stability comparisons. Strands are sequentially colored from blue to red, and for the orange layer configurations, side chain packing is shown with space-fill spheres. The stabilities of the six different variants correlate strongly with the configurations in the hydrophobic packing layer. Courtesy Po-Ssu Huang.
The benefit of this setup (submit locally, compute globally) is that a group can maintain their local host – and still manage users, access, and upgrades – but not have to worry about maintaining the entire OSG computing infrastructure.
“What we do involves computational algorithms, but at the same time everything we design is actually tested here in the lab. We take virtual simulations to practical applications — turning these molecules into new functional molecules for the real world,” says Huang. “The TIM-barrel computational model is an example of taking what we learn to build new proteins for other applications.”
Applications include disease sensors and drug detectors using proteins as binders for small molecules.
“The Holy Grail here is to understand enough to build new things,” Huang says. “This breakthrough has implications for neuroscience, industrial applications, biotech, enzymes for drug delivery, vaccines for HIV, and proteins that can inhibit Ebola. It’s just a huge field. This is where computer simulation comes in, and the faster the better. The OSG definitely fits the need.”
See the full article here .
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