Scientists at the University of Texas Health Science Center at Houston Medical School used supercomputer simulations to demonstrate that Ras proteins, a group of proteins linked to cancer, cluster together, forming aggregates that distort the cell membrane, a discovery that could have implications in the design of new anticancer drugs.
The majority of human cancers are associated with mutations in Ras proteins, making it one of the major targets in drug development. The gene encoding for this protein was first discovered in the 1960s, in a rat sarcoma virus, and was the first gene to be recognized as having the ability to cause cancer in humans.
Ras proteins are mediators of a cascade of cell signals that ultimately cause enhanced cell proliferation and eventually cancer, and these scientists believe that the small, nano-sized clusters formed on the cell membrane which assemble and disassemble quickly, are involved in such signal transmissions. To understand how Ras proteins cluster together and interact with other proteins could prove of immense value.
The research team created coarse-grained molecular dynamics simulations using the Lonestar and Stampede supercomputers at the Texas Advanced Computing Center at UT Austin, and they observed that these Ras protein clusters have a major remodeling effect on the cell membrane, making it fold in the areas closer to the clusters.
Priyanka Srivastava, a postdoctoral researcher involved in the study said “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”. In fact, the team tried to use snapshots of the moving protein to attach small molecules, such as anticancer drugs, in a virtual screening setting.
Previous attempts have been made to inhibit Ras proteins in cancer cells, however the experimental compounds failed because Ras proteins always found a way to compensate for the effect of such drugs. Only recently has interest in finding new Ras targets emerged, partly due to simulations and analyses facilitated by supercomputers.
Finding new membrane binding sites on Ras will result in a bigger understanding of how its on-off switch is controlled and how to stop the uncontrolled cell growth seen in cancers caused by defects in Ras.
This study, led by Dr. Alemayehu Gorfe, assistant professor of Integrative Biology and Pharmacology at the UT Health Medical School was published in the Journal of Physical Chemistry Letters in April 2014 and funded by the National Institutes of Health.