Epilepsy And Alzheimer's Research May Benefit From The Solving Of A Molecular Mystery

Main Category: Neurology / Neuroscience
Also Included In: Epilepsy;  Alzheimer's / Dementia
Article Date: 26 Aug 2007 - 10:00 PDT

email to a friend   printer friendly   opinions  

Carnegie Mellon University chemists have solved a decade-long molecular mystery that could eventually help scientists develop drug therapies to treat a variety of disorders, including epilepsy and Alzheimer's disease. Using intensive theoretical and computational calculations, Carnegie Mellon researchers have modeled the initial molecular changes that occur when the neurotransmitter glutamate docks with a receptor on a neuron, which sets in motion a chain of events that culminates in the neuron firing an electrical impulse.

Tatyana Mamonova, a postdoctoral fellow in Assistant Professor Maria Kurnikova's laboratory at Carnegie Mellon, presented this report at the 234th national meeting of the American Chemical Society in Boston.

Glutamate receptors, which are proteins found in neurons, form a channel through the neuron's membrane. When glutamate, a signaling molecule released by other neurons, docks with the glutamate receptor, it causes a series of molecular shape changes that eventually open the channel and excite the neuron. Although the structure of the glutamate receptor's docking site was known, no one knew precisely which atomic interactions between glutamate and the receptor caused the receptor to change its conformation -- until now.

"The docking site (or ligand binding domain) closes when glutamate binds to it. Tatyana found two key electrostatic interactions that lock the ligand-binding site in its closed form once the ligand is bound," said Kurnikova. "With this knowledge in hand, we can now model binding-site closure and opening using a computer."

Being able to simulate this conformational change is critical to understanding how binding regulates the protein channel, Kurnikova added. "Ultimately, we could use the computer model to design a drug that either inhibits or enhances the activity of the glutamate receptor. Typically, pharmaceutical companies may scan hundreds of potential drugs to find one that has the desired affect. Determining how drugs interact with the glutamate receptor's ligand-binding domain in a computer model would save tremendous time and money in the drug-development process."

To pinpoint the molecular mechanism that switches the binding domain's conformation from open to closed, Mamonova used a variety of chemical-modeling techniques, including molecular dynamics simulations, continuum electrostatics studies, and rigidity and hydrogen-bond analyses. Many of these tasks are theoretically and computationally intensive, and Mamonova frequently relied on the high-performance computing power at the Pittsburgh Supercomputing Center, a joint effort of Carnegie Mellon and the University of Pittsburgh together with Westinghouse Electric Company.

This work is funded in part by the National Institutes of Health and a National Science Foundation Partnerships for Advanced Computational Infrastructure award.

For more information on the Kurnikova group's research, visit http://crete.chem.cmu.edu/. For more on the Pittsburgh Supercomputing Center, see http://www.psc.edu/.

###

About Carnegie Mellon: Carnegie Mellon is a private research university with a distinctive mix of programs in engineering, computer science, robotics, business, public policy, fine arts and the humanities. More than 10,000 undergraduate and graduate students receive an education characterized by its focus on creating and implementing solutions for real problems, interdisciplinary collaboration, and innovation. A small student-to-faculty ratio provides an opportunity for close interaction between students and professors. While technology is pervasive on its 144-acre Pittsburgh campus, Carnegie Mellon is also distinctive among leading research universities for the world-renowned programs in its College of Fine Arts. A global university, Carnegie Mellon has campuses in Silicon Valley, Calif., and Qatar, and programs in Asia, Australia and Europe. For more, see http://www.cmu.edu/.

Source: Amy Pavlak
Carnegie Mellon University

• Additional
• References
• Citations