Polymer models for sheared VWF at surfaces

VWF是一种存在于血液中的大的多聚体蛋白，在正常流动条件下呈球形，但在升高的剪切或拉伸流动中展开并因此被激活。在第一个资助期内，我们使用了一个均聚链作为动态VWF行为的模型，并详细研究了剪切流中吸附均匀和非均匀表面时内聚力和粘附力之间的竞争。由于我们广泛的布朗流体动力学模拟和全局参数变化，我们获得了具有几种不同动态状态和转换的状态图，这取决于剪切速率以及粘合剂和内聚强度等特征参数。在滚动和滑动状态之间的转变，以及长扁形状的转变已经被检测和表征。最相关的是！目前，对于完全基于保守能量势的一般粗粒简单聚合物模型，我们没有发现剪切诱导的吸附转变，即流体动力剪切总是有利于单个球形或卷曲聚合物的解吸状态。这与实验结果相反，因此表明，为了获得剪切诱导的吸附行为，具有长寿命的防滑捕获键可能是必要的成分，这与先前的理论假设一致。在目前的提案中，我们计划在之前资助期的基础上扩展我们的研究，朝着更现实地描述VWF畴结构和VWF与表面之间键的动态特性的方向发展。首先，我们将考虑由于结合位点饱和和屏蔽导致的黏附和内聚之间的竞争，这可能导致在剪切流动中黏附的vwf内键被削弱或断裂的情况下，表面黏附增强的可能性。这可能构成剪切诱导吸附增强的物理（即基于电位的）机制，而无需假设表面捕获键。第二个目标是了解聚合物系统的吸附机制，当表面键由随机开关反应动力学建模时，包括捕获键和滑动键的可能性。特别是，我们将确定剪切流增强表面吸附的结合速率和捕获键参数的范围。使用这种随机表面键模型的吸附行为将与我们基于电位的聚合物模型进行比较。最后，在剪切作用下聚合物链上的单体间力分布将被确定，并用于预测剪切VWF的酶的裂解效率。

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. ln 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 homogeneaus and inhomogeneaus 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 an the characteristic parameters such as shear rate as weil as adhesive and cohesive strengths. Transitions between rolling and slipping states as weil as prolate-oblate shape transitions have been detected and characterized. Most relevantly for the !Jresent proposal, for a generic coarse-grained simple polymer model that is entirely based an a conservative energy potential, we da 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 cantrast with experimental findings and thus demonstrates that in order to obtain shear-induced adsorption behaviour, slip-resistant catch-bonds with lang lifetimes might be a necessary ingredient, in line with previous theoretical assumptions.ln 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 Iead 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. ln 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.