Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
Biophys J. 2013 Dec 3;105(11):2528-40. doi: 10.1016/j.bpj.2013.10.009.
The structure and free energy of multistranded linear polymer ends evolves as individual subunits are added and lost. Thus, the energetic state of the polymer end is not constant, as assembly theory has assumed. Here we utilize a Brownian dynamics approach to simulate the addition and loss of individual subunits at the polymer tip. Using the microtubule as a primary example, we examined how the structure of the polymer tip dictates the rate at which units are added to and lost from individual protofilaments. We find that freely diffusing subunits arrive less frequently to lagging protofilaments but bind more efficiently, such that there is no kinetic difference between leading and lagging protofilaments within a tapered tip. However, local structure at the nanoscale has up to an order-of-magnitude effect on the rate of addition. Thus, the kinetic on-rate constant, integrated across the microtubule tip (kon,MT), is an ensemble average of the varying individual protofilament on-rate constants (kon,PF). Our findings have implications for both catastrophe and rescue of the dynamic microtubule end, and provide a subnanoscale framework for understanding the mechanism of action of microtubule-associated proteins and microtubule-directed drugs. Although we utilize the specific example of the microtubule here, the findings are applicable to multistranded polymers generally.
多股线性聚合物末端的结构和自由能随着单体的加入和损失而变化。因此，聚合物末端的能量状态不是恒定的，这与组装理论的假设不同。在这里，我们利用布朗动力学方法来模拟聚合物尖端单体的加入和损失。我们以微管为例，研究了聚合物尖端的结构如何决定单位从单个原纤维添加和损失的速率。我们发现，自由扩散的单体较少地到达滞后原纤维，但结合更有效，因此在锥形尖端内，领先和滞后原纤维之间没有动力学差异。然而，纳米尺度上的局部结构对添加速率有高达一个数量级的影响。因此，跨微管尖端的动力学结合速率常数（kon,MT）是变化的单个原纤维结合速率常数（kon,PF）的集合平均值。我们的发现对动态微管末端的灾难和救援都有影响，并为理解微管相关蛋白和微管导向药物的作用机制提供了一个亚纳米尺度的框架。虽然我们在这里使用了微管的具体例子，但这些发现适用于多股聚合物。
