Watching a Molecule Bind

Like a paper clip being pulled to a magnet, a small molecule called ADP gets pulled into its port in a new simulation. Because of a simple case of opposites attract, it’s the first time computational biochemists have successfully simulated a molecule—or ligand—being drawn into its binding site in an unbiased simulation.  
“Nobody has been able to capture and describe the full process of ligand binding to a binding site while permitting natural motion of the ligand,” says Emad Tajkhorshid, PhD, assistant professor of biochemistry, pharmacology and biophysics at the University of Illinois at Urbana-Champaign. “We think we are getting the most faithful representation of the binding site, because in our simulations, the protein is dynamic and allowed to freely react to and establish new interactions with the ligand as it binds.” Tajkhorshid and graduate student Yi Wang describe their simulations in the July 15, 2008 issue of the Proceedings of the National Academy of Sciences.
Tajkhorshid and Wang simulated the binding of adenosine disphosphate (ADP), a molecule involved in fueling the cell, to the ADP/ATP carrier protein (AAC) located in the membrane of mitochondria—the cell’s power generation plants. For ADP to be shuttled into the mitochondria, it must first float into a cavity inside AAC and bind to it—an event that lasted 100 nanoseconds in the simulations.
Previously, simulations of molecular binding have required an active force to produce the attachment. But placing the ligand (in this case ADP) at the mouth of the ligand binding site (here, the AAC cavity) in molecular dynamics simulations is more faithful to biological reality. Initially, Tajkhorshid thought that the ADP would just float away. Instead it moved right into place. He and his colleagues found that AAC uses a special bait to lure ADP to its binding site: Positively charged amino acids line the sides and bottom of the AAC cavity, creating a surprisingly strong electrostatic potential that attracts the negatively charged ADP. They called this process “electrostatic funneling.” And because of it, no additional forces are needed in the simulations of ADP binding to AAC.
In addition, when the team scanned the amino-acid sequences of other molecules that shuttle negatively charged molecules across mitochondrial membranes, they found large numbers of positively charged amino acids not present in other membrane proteins, Tajkhorshid says. He suspects these other carriers also use electrostatic funneling to pull in their molecular quarries.
Alan Robinson, PhD, a researcher at the Medical Research Council Dunn Human Nutrition Unit in Cambridge, U.K., says Tajkhorshid has “published what looks like the most reasonable structure of ADP bound to the carrier.” This structure may serve as the starting point for more detailed studies of how ADP binds to AAC and how it triggers the protein to open, he says.


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