Supercomputing simulations crucial to study of Ras protein

Supercomputer simulations have shown clusters of a protein linked to cancer warp cell membranes, an advance that could help design new anticancer drugs, scientists, including one of Indian-origin, say.
Researchers created coarse-grained molecular dynamics simulations of the Ras protein using the Lonestar and Stampede supercomputers at the Texas Advanced Computing Center (TACC), part of The University of Texas at Austin.
More than one-third of all human cancers are associated with somatic, or post-conception, mutations in Ras proteins.
"Mutations on one of the Ras proteins, Kristen or K-Ras, are responsible for 90 per cent or more of pancreatic cancer cases," said Alemayehu Gorfe, assistant professor of Integrative Biology and Pharmacology at the UTHealth Medical School.

The researchers hope that a better understanding of how Ras proteins cluster together and interact with other proteins in cells will bring them one step closer to developing therapeutic targets for Ras-driven tumours.
Gorfe's computer simulations showed Ras proteins cluster together, or form aggregates, on the cell membrane.

"Would the proteins just sit passively and not affect the membrane at all? Or would they somehow change its shape? That is the question we asked," Gorfe said.
"The observation was clearly that they have a major effect on the membrane," Gorfe said.
When the normally flat bilayer of the cell membrane gets drastically curved, scientists call it membrane remodelling.

Membrane remodelling typically occurs during cell division, during cell movement as it slithers around, and during vesicle formation.
On a smaller scale, the membrane folds and buckles near clusters of Ras proteins. Gorfe said that understanding the dynamics of Ras proteins is critical to its study as a potential drug target for cancer.
"Our ultimate goal is to identify novel pockets that transiently open during protein motion but are hidden in the average experimental Ras structure so that we can target those," said Priyanka Srivastava who researches the Ras protein with Gorfe in his lab as a Keck Postdoctoral Fellow at UTHealth.

"Using TACC resources, we carried out an atomic-level simulation of membrane-bound K-Ras.
"And it was very interesting that it actually revealed new binding sites that had not been previously characterised.
"At this point in time we are doing site-directed virtual screening against these sites, which may result in some sort of promising anticancer drug," she said.