Kraken will be officially retired and no longer accessible on August 27, 2014. For more information see Kraken Decommission FAQs.
Kraken will be officially retired and no longer accessible on August 27, 2014. For more information see Kraken Decommission FAQs.
The National Institute for Computational Sciences

Three UT Professors Combine ORNL Neutrons with UT Knoxville Superconducting Magnet and Supercomputing to Probe Enzyme Function

FOR IMMEDIATE RELEASE:

OAK RIDGE, Tenn.—A team of three professors at the University of Tennessee, Knoxville (UTK), has combined high-tech experiments with supercomputing to probe the function of critical enzymes.

Jeremy Smith, Nitin Jain, and Jerome Baudry of the Department of Biochemistry and Cellular and Molecular Biology recently applied the experimental technologies of neutron scattering at ORNL and nuclear magnetic resonance (NMR) spectroscopy at UTK in concert with molecular dynamics (MD) supercomputer simulations involving the NICS Kraken supercomputer to gain an in-depth understanding of motions in cytochrome P450.

Cytochrome P450s are highly effective biocatalysts present in almost all higher organisms. In humans, they increase the rate of chemical reactions involved in the processing of drugs, formation of fats and steroids, development of cancerous cells, and breaking down of pollutants.

Cytochrome P450s are inherently very flexible enzymes and this flexibility is key in how they metabolize a multitude of foreign chemicals such as drugs. Understanding the various internal motions these enzymes undergo to bind different drugs will aid in the design of medicines. This is because drug designers will be able to predict how specific drug candidates will interact with these enzymes and whether they will eventually fail due to chemical interaction with P450s in the patients’ cells.

This research required collaboration between the three laboratories, each with its own expertise in one of three respective areas: neutron scattering, NMR, and computer simulations. Such an integration was necessary to obtain a detailed picture of the motional dance P450s undergo to achieve binding to a target.

The results of their study will soon be published in Biophysical Journal as “Coupled Flexibility Change in Cytochrome P450cam Substrate Binding Determined by Neutron Scattering, NMR and Molecular Dynamics Simulation.”

“The question of how flexible P450s are and how that relates to their function has long puzzled scientists in the drug metabolism area,” Jain said.“ Being able to demonstrate and utilize the complementary nature of the three technologies to address this important question in one P450 now opens up doors to study dynamic aspects of other human drug-binding P450s, with enormous potential in application to drug design.” “The work involving the three UTK professors illustrates how modern research has become highly collaborative, with each faculty member bringing specific expertise integrated into finding a specific solution,” Smith said. “Also, it illustrates how major local facilities such as supercomputing and neutron sources can be combined for the performance of leading-edge research.”

The neutron scattering experiments were conducted using the BASIS and CNCS instruments at the Spallation Neutron Source at ORNL and the HFBS instrument at the National Institute of Standards and Technology (NIST). Assistance was provided by Eugene Mamontov of ORNL with BASIS, George Ehlers of ORNL with CNCS, and Madhu Tyagi of NIST with HFBS. Liang Hong and Nikolai Smolin of the UT/ORNL Center for Molecular Biophysics provided code for analysis and discussions.

NMR experiments were carried out at the high-field NMR facility of UTK, which operates a NMR spectrometer with a 600 MHz superconducting magnet. NMR is a technique that allows scientists to look at molecules very much like its sibling technique MRI, or magnetic resonance imaging, allows physicians to see the internal structures of the human body.

For the MD computer simulations, the research team employed the Kraken, Franklin, and Hopper supercomputers. Kraken, which is managed by NICS for the National Science Foundation (NSF), is a Cray XT5 capable of more than a petaflop—a thousand trillion calculations per second.

The professors’ research team is composed of Yinglong Miao, Zheng Yi, Carey Cantrell of UTK’s Department of Biochemistry and Cellular and Molecular Biology; and Dennis Glass of the UT Graduate School of Genome Science and Technology. All of the researchers except for Cantrell and Jain are also affiliated with the UT/ORNL Center for Molecular Biophysics. A NSF award supported this research project.

About NICS: The National Institute for Computational Sciences (NICS) operates the University of Tennessee supercomputing center, funded in part by the National Science Foundation. NICS is a major partner in NSF’s Extreme Science and Engineering Discovery Environment, known as XSEDE. The Remote Data Analysis and Visualization Center (RDAV) is a part of NICS.