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Enzymes prove no match for supercomputers

Since phospholipase A2 (PLA2) enzymes play a role in many inflammatory diseases, it stands to reason they can usher in a new class of anti-inflammatory medication. To better understand these enzymes and help drive therapeutic drug development, researchers at the University of California, San Diego (UC San Diego) School of Medicine went to the Pittsburgh Supercomputing Center to develop 3D computer models. These visualizations show exactly how two PLA2 enzymes extract their substrates from cellular membranes.

“This is the first time experimental data and supercomputing technology have been used to visualize an enzyme interacting with a membrane,” says Edward Dennis, senior author of the study funded by the US National Institutes of Health, US National Science Foundation, and Howard Hughes Medical Institute.

“We discovered that binding the membrane triggers a conformational change in PLA2 enzymes. We also saw several important differences between the two PLA2 enzymes we studied — findings that could influence the design and development of specific drugs for each enzyme.”

The computer simulations of PLA2 enzymes developed by Dennis and his team, including first author Varnavas Mouchlis, show the specific molecular interactions between PLA2 enzymes and their substrate, arachidonic acid (an inflammatory medium commonly referred to as AA), as the enzymes suck it up from cellular membranes.

3D computer model of phospholipase A2 enzyme extracting its substrate from cell membrane. Courtesy UC San Diego Health Sciences.

Make no mistake — the animations of PLA2 in action are not mere cartoons. They are simulations of sophisticated molecular dynamics based upon previously published deuterium exchange mass spectrometry (DXMS) data on PLA2. DXMS is an experimental laboratory technique that provides molecular information about the interactions of these enzymes with membranes.

To run their molecular dynamic simulations, the team looked to the speed provided by the Anton supercomputer, a 512-node machine at the Pittsburgh Supercomputing Center designed by D.E. Shaw Research specifically for biomolecular simulations. Dennis’s team also relied on the 1,024 compute nodes and 64 I/O nodes of the Gordon machine, managed by the San Diego Supercomputer Center (SDSC) at UC San Diego. 

Each simulation took approximately 10 days, Mouchlis says, and would have been very time consuming on less powerful computer clusters.

“We’ve shown that rigorous experimental data and supercomputer modeling combine to make a very powerful tool,” Mouchlis says. “The experimental data guided the development of accurate 3D models, demonstrating that these two scientific fields can inform one another.”

The liberation of AA by PLA2 enzymes, as shown in these simulations, sets off a cascade of molecular events leading to inflammation. Aspirin and many anti-inflammatory drugs inhibit the enzymes that rely on PLA2 enzymes to provide them with AA. PLA2 enzymes could also be targeted to dampen inflammation at an even earlier point in the process.

“Through computer-aided drug design, our models can assist inhibitor development for PLA2 enzymes,” says Mouchlis. “We believe these enzyme inhibitors can benefit people suffering from arthritis, asthma, and atherosclerosis.”

The new tool is described in the January 26 issue of the Proceedings of the National Academy of Science.Denis Bucher, UC San Diego, and J. Andrew McCammon, UC San Diego and Howard Hughes Medical Institute, were co-authors of the study.

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