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20Lawrence Livermore National LaboratoryS&TR July/August 2008Research Highlightsenvironment will alter the structure of a membrane protein to such an extent that it becomes nonfunctioning,” says computational chemist Richard Law, also in the CMELS Directorate. “In addition, these proteins are hydrophobic. To hide from water, they stick together and form a ‘blob,’ making it impossible to figure out how they function.” Because membrane proteins are insoluble, their structures cannot be easily mapped by x-ray crystallography, a technique commonly used to examine protein structures. Of the more than 45,000 protein structures known today, less than 1 percent are membrane proteins. To capture these proteins, scientists are constructing nanolipoprotein particles (NLPs) in the laboratory and using them as surrogates for cell membranes. NLPs are similar to the high- and low-density lipoprotein particles in the bloodstream—the “good” and “bad” cholesterol that moves fats and lipids through our bloodstream—and they mimic the membrane protein’s natural cellular environment. Because NLPs are smaller and more stable in aqueous environments than the hydrophobic cell membranes, they offer an excellent platform for studying the structure and function of membrane proteins.HUMAN disease caused by pathogens such as viruses and bacteria often results in infection. Infectious diseases may, in turn, affect human proteins and alter cellular function. Although researchers are still learning how those changes occur, the pharmaceutical industry often develops drugs to treat diseases by observing cell behavior. Nearly 60 percent of current drug molecules target proteins on the surface of cell membranes and partition the membrane’s intracellular components from its extracellular environment.Membrane proteins are involved in an array of cellular processes required for organisms to survive, including energy production, communication between cells, and drug interactions. “Membrane proteins are the first responders or mediators for what passes through every cell in our body,” says Livermore chemist Paul Hoeprich, who works in the Chemistry, Materials, Earth, and Life Sciences (CMELS) Directorate. “They connect the outside world to the inside cellular world.” Membrane proteins are exceptionally difficult to study partly because they are insoluble and tend to aggregate or precipitatewhen removed from their natural environment. “A change in Simulating the Biomolecular Structure of Nanometer-Size Particles(a) Computer simulations show chains of the apolipoprotein E4-22K, where colors denote numbering from one end of a molecule (blue) to the other (red).(b) When chains link together around a group of lipids (green), they form a nanolipoprotein particle (NLP). Here, red, white, and blue denote individual folded proteins.An animated NLP is available online at www.llnl.gov/str/JulAug08/videos/nanolipoprotein.swf.(a)(b)