The molecular basis of VWF mechano-sensoring: Structure and interactions of VWF domains as the basis for regulation and aggregation

• Applicant: Professorin Dr. Frauke Gräter
• Subject Area: Bioinformatics and Theoretical Biology ; Biophysics
• Term: from 2011 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 172540668

The function of von Willebrand factor, including adhesion and network formation, is tightly regulated by mechanical force, the molecular mechanism of which has remained elusive to a large extent. We recently have successfully put forward a new mechanism for the force-dependence of the VWF-platelet interaction. In this scenario, which is validated by experiments, VWF A1-GPIb binding is inhibited by a specific A1-A2 interaction, which is relieved by force due to shear flow. In the second funding period, we will extend our approach combining molecular modeling and Force-probe Molecular Dynamics simulations to the interaction of VWF A1 and A3 with collagen, for which we hypothesize a similar scenario. Secondly, as a major step towards a comprehensive understanding of the force-sensoring function of VWF, we aim at structural models and dynamic data under force of the C and D domains of VWF. We will attempt to explain on a molecular level the observed increased aggregation of VWF carrying polymorphism in the C4 domain. Finally, we will develop a coarse-grained Go-type polymer model, in which disulfide bonds can be reversibly broken and formed, in order to decipher mechanisms of force-dependent disulfide bond shuffling in D-domains, which carry protein disulfide isomerase motifs. Our work will contribute to the molecular-level understanding of how collective networks of wild-type and mutant VWF map to clinical presentation.

• DFG Programme: Research Units
• Subproject of: FOR 1543: Shear Flow Regulation of Hemostasis - Bridging the Gap between Nanomechanics and Clinical Presentation
• Co-Investigator: Privatdozent Dr. Carsten Baldauf