A new study reveals in atomic detail how a blood protein that is a fundamental building block of blood clots gives them their life-enhancing, or life-endangering, properties.
The study, conducted by researchers at the University of Illinois and the Mayo College of Medicine, appears in the journal Structure.
Fibrinogen molecules form elastic fibers, the main material of blood clots. When a blood vessel is ruptured, signaling proteins in the blood convert fibrinogen into its active form, called fibrin. Fibrin molecules link together in a scaffold of fibers that seals the vesicle. Cells in the blood, such as red blood cells, fill the gaps.
Fibrinogen is highly elastic, able to reversibly stretch to two or three times its original length.
“Once they’re formed, blood clots have to be elastic because they have a mechanical function to withstand blood pressure,” said Klaus Schulten, holder of the Swanlund Chair in Physics at Illinois.
Understanding what gives fibrinogen its flexibility could help in the design of drugs to enhance their function, he said.
“We investigated what makes blood clots elastic,” said Eric Lee, a graduate research assistant and student in the M.D./Ph.D. program at Illinois. “How do we make them easier to break up or make them less likely to rupture?”
Bernard Lim, a cardiologist at Mayo and an expert on the science of blood clots, contacted Schulten’s group in 2006 for help with a puzzling finding. Lim had conducted a series of experiments using atomic force microscopy to measure the amount of force required to stretch individual fibrinogen molecules.
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: email@example.com.
Klaus Schulten | University of Illinois
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Researchers Discover New Anti-Cancer Protein
22.03.2018 | Universität Basel
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
22.03.2018 | Trade Fair News
22.03.2018 | Earth Sciences
22.03.2018 | Earth Sciences