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Computer models of enzyme function are revealing how nature's biochemical gadgets operate. The world's smallest Rube Goldberg devices are manufactured by Mother Nature. Known as enzymes, these fiendishly complex proteins perform life's most basic tasks–transforming air and food into tissues and metabolic energy. Like Rube's ridiculous contraptions, they have parts that grip and bend, swing and rotate. But in place of ball bearings, dominoes, and springs, enzymes use amino acids to accomplish their feats.
How enzymes operate, however, has proven daunting to decipher. For one thing, they're too tiny to be observed by the most powerful microscopes. For another, they're constantly in motion, flexing and drifting in the soupy innards of a cell. Scientists have long relied on static snapshots (x-ray crystallography) and protein sequences to gain insights into enzyme structure and function. But using this information is like reconstructing a car engine from a parts list and a glance below the hood; it's impossible to understand how it works until you see it running. Now scientists are doing the next best thing: animating enzymes with models run on supercomputers. Using molecular dynamics modeling, scientists can track the behavior of each of the tens of thousands of atoms that make up enzymes, solvents, and substrates–and watch nature's microdevices in action. A Tough Nut To Crack
Among those taking this tack are Zaida Luthey-Schulten, professor of chemistry at the University of Illinois at Urbana-Champaign, and Rommie Amaro. Amaro recently completed her PhD with Luthey-Schulten and is starting a post-doc at the University of California at San Diego. They are using NCSA supercomputers to model the workings of an enzyme that helps manufacture the amino acid histidine. Together with the experimental group of V. Jo Davisson, professor of medicinal chemistry at Purdue University and his student, Rebecca Myers, Amaro and Luthey-Schulten have recently nailed down a key step in the production of amino acids and the building blocks of DNA. Their work made the cover of the July 2005 issue of Biophysical Journal. "One of the really fabulous things about molecular dynamics simulations is they allow you to see things on an atomistic level. There is no other way to see these types of behaviors right now. And when it's consistent with the experimental results, you can have really profound insights into these systems," Amaro says. The enzyme in their sights has a name as complex as its function: imidazole glycerol phosphate (IGP) synthase. The enzyme "is really the epitome of complexity in enzyme catalysis," Amaro says. Its job is to make both IGP and AICAR, an ingredient necessary to make DNA and RNA. Previous research had shown that IGP synthase consists of two parts, hisH and hisF. Each subunit performs half of the enzyme's duties: hisH transforms the abundant amino acid glutamine into ammonia and glutamate, while hisF uses the ammonia to produce IGP and AICAR. Though the two subunits might appear to act independently, they always remain docked together when the enzyme is active. The reason behind their close association appears to be ammonia. If released from the enzyme and into the cell, ammonia would instantly react with water and other solvent molecules. Its escape would leave hisF bereft of a substrate. Instead, the scientists realized, ammonia must follow a protected path within the enzyme to travel from hisH to hisF.
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