Trojan Peptide

How Tat crosses the lipid bilayer--with help from the bilayer.

A powerful snippet of protein called the Tat peptide ferries itself across cell membranes dragging just about anything it’s attached to along with it. How it accomplishes this feat has been a puzzle for a decade. Now, computational simulations offer a detailed picture of how the string of eleven amino acids cajoles the membrane’s lipid bilayer into doing most of the work.


“I was expecting that the peptide would act like a snake going through a hole,” says Angel Garcia, PhD, professor of biocomputation and bioinformat- ics at Rensselaer Polytechnic Institute, who helped design the simulations. Yet his laboratory’s simulations suggest that instead of the snake doing all the work, it is as if the ground makes space for the snake to pass. “I wasn’t expecting the lipids to change so drastically,” he adds.  “Once you see it, of course, it could not be any other way.” The work was published in Proceedings of the National Academy of Sciences in December 2007.


The Tat peptide, discovered on an HIV protein, is part of a potent group of cell-penetrating peptides sometimes called Trojan horse peptides. They haul drugs, proteins or DNA right across the lipid bilayer and into the cell. The myriad uses of such peptides in both therapy and research are not hard to imagine. But how these highly charged, water-loving bits of protein so readily cross the waterless middle of the lipid bilayer has evaded answer for years.


Garcia and postdoctoral fellow Henry Herce, PhD, decided to apply the power of a new computer center at RPI to conduct molecular dynamics sim- ulations of the Tat peptide as it approaches and crosses a lipid bilayer.


At left, four Tat peptides (red) cluster on one side of a lipid bilayer (white) attracted to the phosphate groups (yellow). As the Tat peptide reaches toward phosphate groups on the opposite side (middle), the bilayer thins enough for a chain of water molecules (blue) and the peptide to pass through the membrane (right). Courtesy of Angel Garcia. Reprinted from Proceedings of the National Academy of Sciences 104:52 (2007).Over and over again, the simulations reveal how the peptide induces a change in the bilayer. Because six of the eleven amino acids in Tat are arginine, a relatively large, positively charged amino acid, researchers knew that Tat would be strongly attracted to the lipid bilayer with its blanket of negatively charged phosphates. But Garcia did not expect that phosphates on both sides of the bilayer—not just on Tat’s side—would align to help neutralize Tat’s charge. The more peptides added to the mix, the greater the influence on the opposite side of the bilayer. As the arginine side chains and distant phosphate groups move toward each other, the bilayer thins until it creates a hole lined with phosphate groups, letting a small chain of water and the peptide pass through.


“The idea that the bilayer is ‘thinned,’ thereby allowing the cationic TAT to touch anionic phosphate head groups on both sides of the membrane was utterly unexpected,” says Steven Dowdy, PhD, a Howard Hughes investigator and professor of cellular and molecular medicine at the University of California, San Diego. Dowdy says the information from Garcia’s computational work will inspire experimental testing of the mechanism. And, he says, it could be very helpful in designing enhanced peptides with increased potential to deliver drugs or DNA where researchers want them.



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