B4 - STAFF B4 - RESEARCH B4 - PUBLICATIONS
     
  
  
        

 

VWF is a large, multimeric protein present in blood that under normal flow conditions has a globular form but in elevated shear or elongational flow unfolds and thereby becomes activated. In the first funding period we have used a homo-polymeric chain as a model for the dynamic VWF behaviour and have investigated in detail the competition between cohesive and adhesive forces at adsorbing homogeneous and inhomogeneous surfaces in shear flow. As a result of our extensive Brownian hydrodynamics simulations and global parameter variation we have obtained state diagrams with several distinct dynamical states and transitions, depending on the characteristic parameters such as shear rate as well as adhesive and cohesive strengths. Transitions between rolling and slipping states as well as prolate-oblate shape transitions have been detected and characterized. Most relevantly for the present proposal, for a generic coarse-grained simple polymer model that is entirely based on a conservative energy potential, we do not find a shear-induced adsorption transition, i.e., hydrodynamic shear always favours the desorbed state of a single globular or coiled polymer. This stands in contrast with experimental findings and thus demonstrates that in order to obtain shear-induced adsorption behaviour, slip-resistant catch-bonds with long lifetimes might be a necessary ingredient, in line with previous theoretical assumptions.

In the present proposal, we plan to extend our studies from the previous funding period in the direction of a more realistic description of the VWF domain structure and the dynamic characteristics of bonds between VWF and the surface. First, we will include the competition between adhesion and cohesion due to binding-site saturation and shielding, which might lead to the possibility of enhanced surface adhesion in the case when cohesive intra-VWF bonds are weakened or broken in shear flow. This could constitute a physical (i.e. potential-based) mechanism for shear-induced adsorption enhancement without the need to postulate surface catch bonds. A second goal is to understand the adsorption mechanism of a polymeric system when surface bonds are modelled by stochastic on-off reaction kinetics including the possibility of catch and slip bonds. In particular we will determine the range of binding rates and catch-bond parameters for which surface adsorption is enhanced by shear flow. The adsorption behaviour using such a stochastic surface-bond model will be compared to our potential-based polymer models. Finally, the inter-monomer force distribution along a polymer chain in shear will be determined and used to predict the cleavage efficiency of enzymes that cut VWF in shear.

 

        
  
  
 
     
B4 - STAFF B4 - RESEARCH B4 - PUBLICATIONS