The National Resource for Biomedical Supercomputing (NRBSC) at the Pittsburgh Supercomputing Center (PSC) just completed soliciting proposals for another round of research with Anton, a special-purpose supercomputer designed by D. E. Shaw Research (DESRES) that has enabled researchers to achieve exceptional results in the simulation of biomolecules.
Anton allows researchers to execute ultra-fast “molecular dynamics” (MD) simulations of proteins and nucleic acids, such as DNA and RNA, over much longer time periods than have previously been accessible to computational study. Insights into biomolecular structure and function facilitated by the use of Anton could potentially lead to the development of new and better therapeutic drugs and other improvements in disease treatment.
“Anton performs MD simulations up to 100 times faster than conventional supercomputers,” says Markus Dittrich of NRBSC, “making it possible for the first time to simulate the behavior of proteins over more than a millisecond of biological time. The availability of these extended timescales has opened a new window on many important biological processes.”
Although Anton machines had been used in DESRES’s own internal research program since late 2008, the NRBSC program—in which DESRES provided an Anton machine without cost for non-commercial research use by scientists —marked the first time one of them has been available to the general biomedical community. Initial funding to cover operational costs of Anton at PSC came from a $2.7 million “Grand Opportunities” grant to NRBSC from the National Institute of General Medical Sciences of the National Institutes of Health. In the first and second rounds of awards, announced in September 2010 and September 2011, Anton time was allocated to a total of 91 research groups by a panel of experts convened by the National Research Council (NRC) of the National Academies. Based in part on research advances made in these first two rounds of allocations, DESRES has extended access to this resource beyond the scheduled end date of August 31, 2012. Third-round allocations will be awarded by an NRC panel in late 2012, and will be made to a combination of new and previous awardees.
Results from this work include progress on the “protein-folding problem,” a widely studied question in molecular biology. Proteins are formed in the cell as a string of amino acids, and over a course of time (hundreds of microseconds or longer, depending on the protein) this shapeless string folds into a specific three-dimensional structure. The ability of a protein with a given amino-acid sequence to fold into its characteristic three-dimensional structure is crucial for living cells; misfolded proteins not only lose their functions, but can also cause diseases, including Alzheimer’s and Huntington’s disease.
Relying on Anton, a team of scientists led by Martin Gruebele and Klaus Schulten of the University of Illinois, Urbana-Champaign, successfully simulated the folding of an 80 amino acid protein (lambda-repressor). Their findings (Journal of Physical Chemistry, April 2012) showed a folded result in good agreement with experiment, and went beyond experiment to show new information about the folded form of the protein.
Out of billions of possible shapes that the protein could assume, the MD simulation shows it arriving at the form it takes in nature. “This field is undergoing a revolution,” says Schulten. “It began with folding very small proteins, but now with Anton, we are able to fold larger, more natural proteins. This is a stepping stone toward solving this very important problem.”
Other research with Anton at NRBSC has led to many new findings and publications, which include:
• insight into the mechanism of the signaling protein integrin, which allows the cell to respond to changes in its environment, such as to instigate blood clotting in response to the stress of an open wound;
• details of how “voltage-sensing domains” in ion-channel proteins—proteins that allow ions, such as potassium and sodium, to flow into and out of cells—change their structure in response to changes in electrical potential;
• details of how a particular G-protein coupled receptor (GPCR), known as rhodopsin, activates in response to light. GPCRs are transmembrane proteins, the malfunction of which is involved in many diseases, and the target protein for approximately 40 percent of all modern medicinal drugs;
• simulations of how a prominent anti-cancer drug, gefitinib, interacts with the epidermal growth factor receptor (EGFR), helping to explain how the drug’s effectiveness has been found to be greatest in cancers with mutated and overactive EGFR.
“We are thrilled about the impact that Anton has had over the last two years”, says Markus Dittrich of the NRBSC, “and we are excited to be able to offer continued access to this great resource for the biomedical community.”