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Molecular biomechanics or mechanobiochemistry

Frauke Gräter is head of the “Molecular Biomechanics” research group at the Institute for Theoretical Studies in Heidelberg. Gräter uses computer-based methods to investigate the mechanical forces acting on biological macromolecules in the nanometre range. Her team was also able to show how highly complex processes such as haemostasis are regulated by shear forces.

Occasionally, surprising new discoveries are made by researchers working at the interface of different disciplines. For example, Dr. Frauke Gräter and her team of researchers were able to show how enzymatic reactions were regulated by mechanical forces. The researchers also discovered a new regulatory mechanism of haemostasis that prevents thrombosis from occurring during wound closure.

Shear forces involved in haemostasis

Gräter’s “Molecular Biomechanics” research group at the Institute for Theoretical Studies (HITS) in Heidelberg used computer simulations to investigate a key protein involved in a signalling cascade that triggers haemostasis. This protein (von Willebrand factor, vWF) is one of the largest proteins found in the blood; it is activated when a blood vessel is injured, docking to the wound where it binds thrombocytes and other proteins to form a primary wound closure to prevent loss of blood. Under normal circumstances, vWF is cleaved before the process leads to thrombosis, i.e. the formation of a blood clot inside a blood vessel that obstructs the flow of blood. However, it was previously not known how this regulatory mechanism worked.

Shear forces expose the predetermined breaking point (green) in the A2 domain of the vWF protein. © HITS

Computer simulations carried out at the HITS have for the first time ever made it possible to determine the distribution of the mechanical forces acting on the protein in the nanometer scale. The findings not only provide an explanation for the process of vWF cleavage, they might also contribute to increasing our understanding of the development of diseases such as thromboses or genetic bleeding disorders.

Shear forces occur in the bloodstream and exert a tension on the vWF protein located on the vessel wall. Turbulences occurring at the site of injury increase the shear forces. This leads the protein to partially unfold and expose an active domain (a kind of predetermined breaking point) to ADAM TS13, a protease that specifically cleaves vWF. "The von Willebrand factor is a kind of force sensor that is activated through high shear forces," explains Gräter.

Silk is stronger than steel

Spider's web © Photo: Michael Goduscheit

Gräter and her team have also analysed the effect of mechanical forces on other proteins. They used computer models to investigate the giant protein titin, which, besides actin and myosin, represents the third major component of muscles, silk proteins of spider webs and silkworm cocoons. Gräter points out that the elasticity and tensile strength of muscles and silk proteins are greater than that of steel. The unique properties of silk fibres are the result of the silk proteins' repetitive sequences of six to nine amino acids, which form parallel and anti-parallel beta-sheet structure piles that are connected with each other by hydrogen bridges. These ordered crystalline repeats alternate with amorphic, deformable structures consisting of non-repetitive amino-acid sequences. Silk proteins of different origin have the same fibre architecture in principle: Spider silk and the cocoon silk of the silkworm caterpillar are the best known silk structures, consisting of highly ordered crystalline alanine sequences (spider silk) or alanine-glycine and glycine-alanine (silkworm cocoon) repeats.

Schematic of the crystalline silk fibre units and the tensile strengths acting on them. In the atom model on the left, the force that is required to pull a unit from the complex is shown as a spring. © Biophysical Journal 2009

The researchers hope that the detailed understanding of the connection between the molecular architecture of silk fibres and their outstanding mechanical properties will enable them to use these findings to produce artificial, custom-made polymer fibres. They have already gained initial insights into the mechanics of silk fibres on the molecular level. The researchers used idealised models of the crystalline domains, where they were able to determine the tensile strength in the nanometre range that is required to break up these stabilising construction elements.

From Shanghai to Heidelberg

The use of silk as a textile fibre dates back to traditions existing in China several thousands of years ago. Frauke Gräter had the idea for her research project on the mechanics of silk fibres when she became head of a junior research group at the CAS-MPG Partner Institute for Computational Biology of the Shanghai Institutes for Biological Sciences in 2007. The Insitute was founded by the Max Planck Society (MPG) and the Chinese Academy of Sciences (CAS). CAS is the Chinese partner of the Max Planck Society.

However, this was not the first time she had lived in China. When she was doing her doctoral thesis at the Max Planck Institute of Biophysical Chemistry in Göttingen, she spent two years at the CAS Institute of Materia Medica in Shanghai. Since moving to the HITS (the former EML Research) in Heidelberg in summer 2009, she regularly returns to Shanghai to maintain her close cooperation with the partner institute, where she still supervises staff in her own research group.

Heidelberg Institute for Theoretical Studies 

The Heidelberg Institute for Theoretical Studies (HITS gGmbH) is a private, non-profit research institute originally known as EML Research gGmbH. On the 1st January 2010 EML Research gGmbH became HITS gGmbH and continued the EML's research on a broader basis. The research institution, funded by the Klaus Tschira Foundation, carries out basic research in different areas of mathematics, natural sciences and computer sciences. The institute's methodological focus centres on the development of theories and models, in which computer-based simulations and data acquisition/analysis play a key role. The HITS has space for approximately 10 research groups working on a broad range of different topics from the fields of theoretical biochemistry, molecular biomechanics, scientific databases, computer linguistics, theoretical astrophysics, medical statistics and many more. Dr. h.c. Klaus Tschira and Prof. Dr.-Ing. Andreas Reuter are the managing directors of HITS gGmbH.

Further information:
Dr. Frauke Gräter
Molecular Biomechanics Group
HITS gGmbH
Schloss-Wolfsbrunnenweg 35
69118 Heidelberg
Tel.: +49 (0)6221-533 267
Fax: +49 (0)6221-533 298
E-mail: frauke.graeter(at)h-its.org
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/molecular-biomechanics-or-mechanobiochemistry