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Cold Neutrons for Biology and Technology

For Immediate Release: February 19, 2002

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Contact: Mark Bello

What’s so hot about “cold” neutrons? Packaged with protons in the atomic nucleus, neutrons are non-destructive, highly penetrating probes, valuable for studying changes in membranes over time. Unlike X-rays, these uncharged particles are especially sensitive to hydrogen and other light atoms that are major components of proteins and cell membranes. With a method called isotopic substitution, researchers can highlight specific regions of large biological molecules and track how these subunits change shape and location.

Behaving like tiny waves of energy, neutrons also make excellent rulers. Depending on temperature, the length of the neutron ruler—which corresponds to the distance between consecutive wave peaks—can be tuned over a range spanning from roughly the size of a single atom to the size of a molecule composed of hundreds or thousands of atoms.

In the case of cold neutrons, which are uniformly chilled by passing them through a reservoir of liquid hydrogen at -232 degrees Celsius (-450 degrees Fahrenheit), wavelengths are comparable to the size of proteins and other important biological molecules. NIST soon will upgrade the “cold source” at its Center for Neutron Research. This will double the intensity of cold neutron beams, which will reduce the time required to complete experiments.

About the NIST Center for Neutron Research (NCNR). The NCNR ranks among the best neutron research centers in the world. In the United States, it is the most versatile source of neutrons for research at a time when growing numbers of industrial and university scientists are finding neutrons essential to accomplishing their research objectives. The center’s 15 cold neutron research instruments, housed in a hangar-sized hall, provide world-class capabilities, and some are recognized as the world’s best. The NCNR supports research in a broad range of areas, including microelectronics, physics, materials science, chemistry, biology, and even art history. In 2001, experiments conducted at the center involved more than 1,700 researchers representing more than 100 U.S. universities, 50 U.S. industrial laboratories, and over 30 government laboratories.

Stephen H. White: UC-Irvine (UCI) professor of biophysics and leader of the CNBT project, White is working to explain the fundamental principles that govern the folding and stability of cell membrane proteins. The ultimate aim of White’s laboratory is to predict the detailed three-dimensional structure of membrane proteins from their constituent sequence of amino acids, the building blocks of proteins. White will use “cold neutron” probes and molecular dynamics simulations to reveal the complex interactions that occur as proteins and protein fragments, first, bind themselves to the sandwich-like cell membrane and, then, assume their final shape. At first, White will focus on two proteins: melittin, a component of bee venom that winds like a corkscrew through the bilayer membrane, and indolicidin, a linear peptide with antibiotic properties.

Huey W. Huang: Professor of physics and astronomy at Rice University, Huang has developed methods for investigating in-plane structures in membranes. Using neutron scattering, he has detected transmembrane pores induced by disease-fighting membrane-active peptides. These antimicrobial peptides can exist in either of two states. In the active state, they form pores in the membrane. In the inactive state, the peptides are embedded in the lipid head groups on the membrane surface. With the CNBT’s instruments, Huang will examine structural changes that occur during the shift from one state to the other as well as factors that trigger the transition. Among the peptides that Huang will study are those related to human defensins—part of the body’s first line of defense against microbe invaders—and those with potential for pharmaceutical applications.

Douglas Tobias: UCI assistant professor of chemistry, Tobias is developing approaches to simulate membrane-protein interactions at the level of individual atoms. His laboratory’s simulations account for such influencing factors as temperature, membrane pressure, and electrostatic forces. Tobias will use data from CNBT experiments as a reality check and to refine and extend the models that underlie his molecular dynamics simulations. Initially, Tobias will focus on melittin, indolicidin, and Vpu, a disruptive protein produced by one type of the AIDS-causing human immunodeficiency virus (HIV-1). Simulation techniques refined or developed during these experiments should be applicable to a wide variety of membranes and proteins.

J. Kent Blasie: University of Pennsylvania professor of physical and biological chemistry, Blasie and his Penn collaborators have developed methods for making simple analogs of complicated membrane proteins. These so-called maquettes are easy to modify—a boon to efforts to determine their structure and mechanism of action compared to their more intricate counterparts. They also are being eyed for use as biomolecular devices. In the CNBT project, Blasie will investigate membrane protein maquettes that perform vectorial electron transfer reactions, and he will study how Vpu, an HIV-1 accessory protein, contributes to the proliferation of the virus in the bodies of infected people.

Susan Krueger and Charles Majkrzak: Krueger, a NIST biophysicist, and Majkrzak, a NIST physicist specializing in instrument design, have pioneered new neutron-based methods for surveying the cell membrane landscape and for measuring its features. This makes it possible to probe membrane-like samples in a fluid environment, akin to conditions in the body. Other payoffs include increased resolution and easier-to-interpret experimental data. They and NIST colleagues recently reported a new, high-resolution technique that may greatly simplify efforts to measure the depth and orientation of peptide fragments within membranes. Krueger and Majkrzak aim to optimize the new technique, using melittin and alpha-hemolysin, a barrel-shaped protein secreted by some strains of staphylococcus bacteria.

Thomas J. McIntosh: Professor of cell biology at the Duke University Medical Center, McIntosh studies how the composition of the two lipid layers that make up cell membranes affects the shape, organization, and binding of proteins. A key area of interest in the CNBT project will be the top-most layer of mammalian skin, which, among other things, influences the effectiveness of drugs and other treatments applied to the skin.

John F. Nagle: Professor of biophysics at Carnegie Mellon University, Nagle aims to explain the organization of lipid molecules in cell membranes. On average, lipids make up about half the mass of a cell membrane, but actual amounts of these fatty acids vary greatly among membrane types. What accounts for this diversity in lipid composition is unknown. To answer this question, Nagle has gathered data using an array of experimental techniques. Without sustained neutron diffraction studies, however, key pieces of information have been out of reach. Ultimately, Nagle intends to construct time-averaged pictures showing how lipids are organized in a cell membrane and to measure nanometer-scale changes in membrane structure.

Anne Plant: A NIST biotechnology researcher, Plant and colleagues have devised methods for making rugged imitations of complex cell membranes. Stable in air and liquid, these membrane mimics can support a variety of research-and-development pursuits: studies of the structure and function of cell-membrane proteins, development of miniature biosensors and diagnostic devices, pharmaceutical screening, and tissue engineering. In addition to furthering her own research on cell-membrane receptors, Plant, along with other scientists in NIST's Biotechnology Division, will supply CNBT collaborators with fabrication and analytical tools.

Other CNBT Collaborators: Stanley Opella, Resource for Solid-State NMR of Protein, University of California-San Diego

Klaus Gawrisch, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health

Michael Klein, Materials Science and Engineering Center, University of Pennsylvania

National Stable Isotope Resource, Los Alamos National Laboratory