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，但在升高的剪切或伸长流动中展开，从而被激活。在第一个资助期，我们使用了均聚物链作为动态VWF行为的模型，并详细地研究了在剪切流动中吸附均匀和非均匀表面的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，我们得到了具有几个不同动力学状态和转变的状态图，这取决于诸如剪切速率如Weil作为粘合强度和内聚强度的特征参数。滚动态和滑动态之间的转变以及扁平-扁平的形状转变已经被检测和表征。对于Jresent的建议，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状或盘状聚合物的脱附状态。这与实验结果一致，从而表明，为了获得剪切诱导的吸附行为，具有长寿命的抗滑捕获键可能是一个必要的成分，这与以前的理论假设是一致的。在本提案中，我们计划将我们的研究从上一个资金阶段扩展到更真实的描述VWF结构和VWF与表面之间键的动态特性的方向。首先，我们将包括由于结合部位饱和和屏蔽而导致的粘附力和内聚力之间的竞争，这可能导致在剪切流中内聚力键被削弱或断裂的情况下增强表面粘附力的可能性。这可以构成剪切诱导吸附增强的物理(即，基于势)机制，而不需要假定表面捕获键。第二个目标是理解当表面键被随机开关反应动力学模拟时，聚合物体系的吸附机制，包括捕获和滑移键的可能性。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的基于势的聚合物模型进行比较。最后，将确定剪切中沿聚合物链的单体间力分布，并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.