Mechanism of blood clot elasticity revealed in high definition

After dozens of trials, Lim had come up with a “force extension curve” that showed how the fibrinogen molecule behaved when it was stretched. His data indicated that the fibrinogen molecule elongates in a sequential fashion, with three distinct phases. But he could not tell which parts of the fibrinogen molecule were involved.

Fibrinogen is a symmetrical molecule, containing a central region connected to two end regions by long, interweaving coiled chains, called alpha helices. These “coiled coils” were believed to give the molecule its elasticity. But how"

The Illinois team used a computational approach to tackle the mystery. Using steered molecular dynamics (SMD), they modeled the behavior of every atom of the fibrinogen molecule as it was stretched. The computation involved more than a million atoms, and required six months to complete.

The resulting simulation (see movie) generated a force extension curve that matched the one Lim had produced.

“This was an incredibly strong piece of evidence that what (Lim) saw wasn’t just in the eye of the beholder, but he saw really a property of the protein,” Schulten said.

The simulation also showed in molecular detail how the fibrinogen molecule responded to stretching. Each phase in the force extension curve corresponded directly with a distinct set of events in the elongation of the molecule.

“The simulations revealed that … the extension occurs in a specific and orderly pattern, with distinct regions within the coiled-coil unraveling before others,” the authors wrote.

Lim had also demonstrated that changes in calcium levels or in the pH (acidity) of a blood clot could alter fibrinogen elasticity, a finding that could influence the design of pharmaceutical agents.

“By understanding what happens at the molecular level, you can understand where to target drugs,” Lee said.

This study points to the efficacy of combining molecular dynamics simulations with experimental data on actual molecules, Schulten said. This is proving to be an effective way to get to the heart of molecular behavior, he said.

Simulations can test important, but potentially ambiguous, experimental findings, Schulten said. “And we can see (the behavior of the molecule) in chemical detail, in atomic detail. We see the full chemistry of this mechanical process.”

Schulten directs the theoretical and computational biophysics group at the Beckman Institute for Advanced Science and Technology.

Editor’s note: To reach Klaus Schulten, call 217-244-1604; e-mail: .

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