Akram Sk Ashif, Brown Tyler, Whitelam Stephen, Meisl Georg, Knowles Tuomas P J, Schmit Jeremy D
Department of Physics, Kansas State University, Manhattan, Kansas.
Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California.
Biophys J. 2025 Mar 4;124(5):778-788. doi: 10.1016/j.bpj.2025.01.018. Epub 2025 Jan 28.
We present a model to describe the concentration-dependent growth of protein filaments. Our model contains two states, a low-entropy/high-affinity ordered state and a high-entropy/low-affinity disordered state. Consistent with experiments, our model shows a diffusion-limited linear growth regime at low concentration, followed by a concentration-independent plateau at intermediate concentrations, and rapid disordered precipitation at the highest concentrations. We show that growth in the linear and plateau regions is the result of two processes that compete amid the rapid binding and unbinding of nonspecific states. The first process is the addition of ordered molecules during periods in which the end of the filament is free of incorrectly bound molecules. The second process is the capture of defects, which occurs when consecutive ordered additions occur on top of incorrectly bound molecules. We show that a key molecular property is the probability that a diffusive collision results in a correctly bound state. Small values of this probability suppress the defect capture growth mode, resulting in a plateau in the growth rate when incorrectly bound molecules become common enough to poison ordered growth. We show that conditions that nonspecifically suppress or enhance intermolecular interactions, such as the addition of depletants or osmolytes, have opposite effects on the growth rate in the linear and plateau regimes. In the linear regime, stronger interactions promote growth by reducing dissolution events, but in the plateau regime stronger interactions inhibit growth by stabilizing incorrectly bound molecules.
我们提出了一个模型来描述蛋白质细丝的浓度依赖性生长。我们的模型包含两种状态，一种是低熵/高亲和力的有序状态，另一种是高熵/低亲和力的无序状态。与实验结果一致，我们的模型显示在低浓度下存在扩散限制的线性生长阶段，随后在中等浓度下出现与浓度无关的平稳期，在最高浓度下则出现快速的无序沉淀。我们表明，线性和平稳区域的生长是两个过程的结果，这两个过程在非特异性状态的快速结合和解离过程中相互竞争。第一个过程是在细丝末端没有错误结合分子的时间段内添加有序分子。第二个过程是捕获缺陷，当在错误结合的分子之上连续进行有序添加时就会发生这种情况。我们表明，一个关键的分子特性是扩散碰撞导致正确结合状态的概率。这个概率值较小时会抑制缺陷捕获生长模式，当错误结合的分子变得足够普遍以至于毒害有序生长时，生长速率就会出现平稳期。我们表明，非特异性抑制或增强分子间相互作用的条件，例如添加耗尽剂或渗透剂，对线性和平稳阶段的生长速率有相反的影响。在直线阶段，更强的相互作用通过减少溶解事件来促进生长，但在平稳阶段，更强的相互作用通过稳定错误结合的分子来抑制生长。
