Mlynarczyk Paul J, Pullen Robert H, Abel Steven M
Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, Tennessee 37996, USA.
J Chem Phys. 2016 Jan 7;144(1):015102. doi: 10.1063/1.4939219.
Positive feedback is a common feature in signal transduction networks and can lead to phenomena such as bistability and signal propagation by domain growth. Physical features of the cellular environment, such as spatial confinement and the mobility of proteins, play important but inadequately understood roles in shaping the behavior of signaling networks. Here, we use stochastic, spatially resolved kinetic Monte Carlo simulations to explore a positive feedback network as a function of system size, system shape, and mobility of molecules. We show that these physical properties can markedly alter characteristics of bistability and stochastic switching when compared with well-mixed simulations. Notably, systems of equal volume but different shapes can exhibit qualitatively different behaviors under otherwise identical conditions. We show that stochastic switching to a state maintained by positive feedback occurs by cluster formation and growth. Additionally, the frequency at which switching occurs depends nontrivially on the diffusion coefficient, which can promote or suppress switching relative to the well-mixed limit. Taken together, the results provide a framework for understanding how confinement and protein mobility influence emergent features of the positive feedback network by modulating molecular concentrations, diffusion-influenced rate parameters, and spatiotemporal correlations between molecules.
正反馈是信号转导网络中的一个常见特征，可导致双稳态和通过结构域生长实现信号传播等现象。细胞环境的物理特征，如空间限制和蛋白质的流动性，在塑造信号网络行为方面发挥着重要但尚未得到充分理解的作用。在这里，我们使用随机的、空间分辨的动力学蒙特卡罗模拟来探索一个正反馈网络，该网络是系统大小、系统形状和分子流动性的函数。我们表明，与均匀混合模拟相比，这些物理性质可以显著改变双稳态和随机切换的特征。值得注意的是，在其他条件相同的情况下，体积相等但形状不同的系统可能会表现出质的不同行为。我们表明，通过簇的形成和生长会发生随机切换到由正反馈维持的状态。此外，切换发生的频率非平凡地取决于扩散系数，相对于均匀混合极限，扩散系数可以促进或抑制切换。综上所述，这些结果提供了一个框架，用于理解限制和蛋白质流动性如何通过调节分子浓度、扩散影响的速率参数以及分子之间的时空相关性来影响正反馈网络的涌现特征。
