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An unprecedented look into the structure and function of cellular membranes could lead to a new array of designer drugs.
At least nine Nobel Prizes have been awarded for scientific research based on neutron science, including the 1994 prize bestowed on physicist Clifford Shull, who pioneered neutron scattering at an ORNL reactor. ORNL's Ian S. Anderson boldly predicts that future discoveries resulting from membrane research at the Laboratory's premier neutron sources could lead to another Nobel Prize. A membrane is a thin, impermeable barrier that encloses a living cell. The cellular membrane is a fluid network of interacting fats, called lipids, criss-crossed by active proteins and other components. These membrane proteins form active channels, sensors, and signaling networks that span the membrane, allowing cells to communicate with the outside world, transport nutrients, and expel waste. "About 70 percent of all drug targets are membrane-incorporated or membrane-associated proteins," says Dean Myles, director of ORNL's Center for Structural Molecular Biology, which conducts experiments at both the High Flux Isotope Reactor and the Spallation Neutron Source. "Research at both of these facilities will focus on fundamental problems, including understanding membranes and how proteins interact with membranes," Myles notes. "Researchers will address problems ranging from the breakdown of plant cell walls for bio-energy to the design of therapeutic drugs that protect us from disease. "In many infections, invading cells release toxins that attack our cell membranes. Neutron scattering can help us determine how and where these toxins attack." Visualizing such interactions can help scientists identify the mechanism of infection and guide pharmaceutical researchers in designing drugs that block toxin-cell interactions. The process often involves isolating these proteins and determining their atomic structures. The unique value of neutrons is their ability to allow researchers to pinpoint hydrogen atoms in these structures with exquisite detail. Because heavier hydrogen atoms scatter neutrons differently, scientists can further heighten the visibility of targeted proteins by replacing their hydrogen atoms with deuterium. Users at ORNL's Bio-Deuteration Laboratory label proteins in living cells with deuterium for neutron "contrast variation" experiments. Labeled proteins stand out like beacons against background solvent or membranes. Researchers can then more easily observe how these highlighted proteins interact and assemble into larger protein complexes and molecular machines, thus contributing to the understanding of how these complex systems work in cells. Biologists use deuterium-labeled lipids to highlight interactions in membranes. Their goal is to determine how and where particular lipids insert in membranes, whether insertions are random or uniform, or, as some evidence suggests, whether particular lipid molecules may coalesce into active units, or "rafts," that travel through the membrane. Cholesterol, for example, is a natural lipid whose interactions with cellular membranes are thought to stiffen them. Deuterium labeling will allow researchers to "see" cholesterol molecules within a lipid sea and to understand their effect on membrane structure and dynamics. Understanding precisely how membrane and protein dynamics relate to their structure and function remains a major scientific challenge. Ken Herwig, ORNL's Neutron Scattering Sciences group leader, is tackling this problem at the SNS, where he compares the motions of proteins from common microbes and of proteins extracted from thermophilic organisms that thrive in hot deepsea vents. Understanding how temperature affects dynamics may help explain the remarkable stability of thermophilic proteins at high temperatures that break down most other proteins. The diverse instrument suite at HFIR and SNS will provide biologists with unique insights into the structure, function, and dynamics of cellular systems. Each year, dozens of researchers will conduct biological research at HFIR using a small-angle neutron scattering (Bio-SANS) instrument. Dozens more will explore biological mysteries at SNS, employing instruments specifically designed to probe dynamics using neutron spectroscopy, or to determine molecular structures using SANS, the liquids reflectometer, and the MaNDi macromolecular diffractometer. "Neutrons are just a small part of the toolset that biologists use," Myles says. "But, in many applications, neutrons provide critical information that is difficult or impossible to obtain using other techniques. "When they do, the result may be a ticket to Stockholm.
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