Polymer models for sheared VWF at surfaces

VWF是存在于血液中的大的多聚体蛋白质，其在正常流动条件下具有球状形式，但在升高的剪切或拉伸流动中展开，从而被激活。在第一个资助期内，我们使用了均聚物链作为动态VWF行为的模型，并详细研究了剪切流中吸附均质和非均质表面的内聚力和粘附力之间的竞争。作为我们广泛的布朗流体动力学模拟和全局参数变化的结果，我们已经获得了具有几个不同的动力学状态和转变的状态图，这取决于特征参数，如剪切速率以及粘附和内聚强度。滚动和滑动状态之间的过渡以及扁长-扁扁长形状的过渡已被检测和表征。最重要的是！对于完全基于保守能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，流体动力学剪切总是有利于单个球状或卷曲聚合物的脱附状态。这与实验结果相矛盾，因此表明，为了获得剪切诱导的吸附行为，具有lang寿命的防滑捕获键可能是必要的成分，与先前的理论假设一致。我们计划从上一个资助期开始，向更真实地描述VWF结构域结构和动态特征的方向扩展我们的研究。VWF和表面之间的键。首先，我们将包括由于结合位点饱和和屏蔽，这可能导致增强的表面粘附力的情况下，当粘性内VWF键被削弱或在剪切流中被打破的可能性的粘附力和内聚力之间的竞争。这可能构成一个物理（即潜在的）机制，剪切诱导的吸附增强，而不需要假设表面捕获键。第二个目标是了解吸附机制的聚合物系统时，表面债券建模随机开关反应动力学，包括捕获和滑动债券的可能性。特别是，我们将确定的结合率和捕捉键参数的范围内，表面吸附增强剪切流。使用这样一个随机的表面键模型的吸附行为进行比较，我们的潜在的聚合物模型。最后，将确定在剪切中沿沿着聚合物链的单体间力分布，并将其用于预测在剪切中切割VWF的酶的切割效率。

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.