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
First SARS-CoV-2 genomes in Austria openly available
03.04.2020 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften
Do urban fish exhibit impaired sleep? Light pollution suppresses melatonin production in European perch
03.04.2020 | Leibniz-Institut für Gewässerökologie und Binnenfischerei (IGB)
Drops of water falling on or sliding over surfaces may leave behind traces of electrical charge, causing the drops to charge themselves. Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz have now begun a detailed investigation into this phenomenon that accompanies us in every-day life. They developed a method to quantify the charge generation and additionally created a theoretical model to aid understanding. According to the scientists, the observed effect could be a source of generated power and an important building block for understanding frictional electricity.
Water drops sliding over non-conducting surfaces can be found everywhere in our lives: From the dripping of a coffee machine, to a rinse in the shower, to an...
90 million-year-old forest soil provides unexpected evidence for exceptionally warm climate near the South Pole in the Cretaceous
An international team of researchers led by geoscientists from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) have now...
The bacteria that cause tuberculosis need iron to survive. Researchers at the University of Zurich have now solved the first detailed structure of the transport protein responsible for the iron supply. When the iron transport into the bacteria is inhibited, the pathogen can no longer grow. This opens novel ways to develop targeted tuberculosis drugs.
One of the most devastating pathogens that lives inside human cells is Mycobacterium tuberculosis, the bacillus that causes tuberculosis. According to the...
An international team with the participation of Prof. Dr. Michael Kues from the Cluster of Excellence PhoenixD at Leibniz University Hannover has developed a new method for generating quantum-entangled photons in a spectral range of light that was previously inaccessible. The discovery can make the encryption of satellite-based communications much more secure in the future.
A 15-member research team from the UK, Germany and Japan has developed a new method for generating and detecting quantum-entangled photons at a wavelength of...
Together with their colleagues from the University of Würzburg, physicists from the group of Professor Alexander Szameit at the University of Rostock have devised a “funnel” for photons. Their discovery was recently published in the renowned journal Science and holds great promise for novel ultra-sensitive detectors as well as innovative applications in telecommunications and information processing.
The quantum-optical properties of light and its interaction with matter has fascinated the Rostock professor Alexander Szameit since College.
02.04.2020 | Event News
26.03.2020 | Event News
23.03.2020 | Event News
03.04.2020 | Materials Sciences
03.04.2020 | Life Sciences
03.04.2020 | Life Sciences