MAPAS computer program spurs drug discovery efforts for neurological diseases.

By Ryan DeBeasi

May 12, 2008 | A new computer program that simulates the binding of proteins to cell membranes could be a boon to researchers investigating Parkinson's and Alzheimer's diseases, cancer, and other conditions. The software, called membrane-associated-proteins assessment (MAPAS - http://cancer-tools.sdsc.edu/MAPAS/pro2.html), can pinpoint the amino-acid residues that make contact with cell membranes. It was developed by researchers at the San Diego Supercomputing Center and the University of California, San Diego, and described in the February issue of Nature Methods.

Users upload a protein database file to the Supercomputing Center via a web-based interface. MAPAS runs on a high-performance computer at the Center, breaking the protein into regions and simulating the minute electrical forces that cause molecules to bind to one another. In about half a day, the program returns data on whether the protein is likely to bind to membranes and which region of the protein may be responsible for this activity. For each region, there is a list of the residues that make it up and a link to a Java applet that gives a three-dimensional, rotatable image of the region.

Igor Tsigelny, a coauthor of the paper, has used the technology to investigate new ways of treating Parkinson's disease. In a paper last year in the Federation of European Biochemical Societies Journal, he and other researchers investigated a protein called α-synuclein, which has been linked to Parkinson's. In some cases, the protein binds to cell membranes and forms a ring-like complex with other α-synuclein proteins. Tsigelny said that this structure can create a pore in the membrane that allows an influx of calcium ions, killing the cell. MAPAS allowed the researchers to determine which parts of α-synuclein were likely to bind to cell membranes and how complexes of the proteins might be structured.

"Without this technology, we wouldn't be able to do this paper," said Tsigelny.

A related protein called β-synuclein could prevent α-synuclein from forming the ring-like complexes that kill cells, the researchers found, suggesting a drug that mimics the effects of α-synuclein. Tsigelny and others are developing a drug. "We have a couple of good candidates," he said. The binding of small proteins to cell membranes is also implicated in Alzheimer's, cancer, and other diseases. "Mostly you want to destroy this membrane binding," he said, but "there are some specific cases where we want to improve binding."

Tsigelny uses a local interface to MAPAS that allows him to change a few coefficients, but is otherwise very similar to the web-based offering. "I think it's very important for people to have [access to MAPAS]," he said. He added that the web-based interface to the program was made available a month or two before the publication of the Nature Methods paper.

What is the next step for MAPAS? "We need to expand it to different types of membranes," said Tsigelny. He added that most research on proteins analyzes them in solution, not integrated into the membrane or binding to it. "Interphase membrane contact is not explored enough."

The program is in beta, hence its utilitarian interface and the often long wait for results. My first three attempts to use the program failed, which Tsigelny said was due to maintenance at the Supercomputing Center. On my fourth attempt, the program returned a detailed analysis of the micelle-bound α-synuclein file that I had uploaded. (Protein database files can be downloaded from http://rcsb.org).

Tsigelny noted that MAPAS has attracted many more jobs than he expected, and he hopes to speed up processing through parallelization and a faster computer. "These things happen more often than you want," said Tsigelny of the maintenance issues. "Welcome to the supercomputing world."

Further Reading:
Sharikov, Y. et al. 2008. Nature Methods. 5, 119 - 119

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 This article appeared in Bio-IT World Magazine.
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