Both PS and PE are abundant in the inner but not the outer leaflets of the double-layered membranes of cells. This keeps these lipids from coming into contact with clotting factors in the blood. But any injury that ruptures the cells brings PS and PE together with the clotting factors, initiating a chain of events that leads to blood clotting.
Researchers have developed many hypotheses to explain why clotting factors bind most readily to PS when PE is present. But none of these could fully explain the data.
In the new study, Morrissey's lab engineered nanodiscs with high concentrations of PS and PE, and conducted functional tests to determine if they responded like normal membranes.
"We found that the nanodisc actually is very representative of what really happens in the cell in terms of the reaction of the lipids and the role that they play," Morrissey said.
Then Tajkhorshid's lab used advanced modeling and simulation methods to position every atom in the system and simulated the molecular interactions on a supercomputer. The simulations indicated that one PS molecule was linking directly to the GLA domain of the clotting factor via an amino acid (serine) on its head-group (the non-oily region of a phospholipid that orients toward the membrane surface).
More surprisingly, the simulations indicated that six other phospholipids also were drawing close to the GLA domain. These lipids, however, were bending their head-groups out of the way so that their phosphates, which are negatively charged, could interact with positively charged calcium ions associated with the GLA domain. (Watch a movie of the simulation.)
"The simulations were a breakthrough for us," Morrissey said. "They provided a detailed view of how things might come t
|Contact: Diana Yates|
University of Illinois at Urbana-Champaign