基因开关翻转的反应坐标
Reaction coordinates for the flipping of genetic switches
摘要：
我们提出了一个详细的分析，基于前向通量采样（FFS）模拟方法，开关的动力学和稳定性的两个模型的遗传拨动开关，由两个相互抑制的基因编码转录因子（TF）;在一个模型中（互斥开关），它们互相排斥对方的绑定，而在另一个模型（通用开关）中，两个转录因子可以同时结合到共享的操纵子区。我们评估了两对影响这些开关稳定性的反应的作用：TF-TF同源二聚化和TF-DNA缔合/解离。我们将翻转率k分解为在两个稳定状态之间的分界面（分界线）处找到系统的概率rho（q*）与动力学前因子R的乘积。在排他性转换的情况下，TF操纵子结合的速率影响rho（q*）和R，而TF二聚化的速率仅影响R。在一般开关的情况下，TF-操纵子结合和TF二聚化都影响k、R和rho（q*）。为了阐明这一点，我们分析了过渡态系综（TSE）。对于排他性开关，改变TF-操纵子结合的速率可以极大地改变开关的途径，而改变二聚化的速率改变开关速率而不改变机制。通用开关的开关途径对TF-操纵子和TF-TF结合的速率常数的变化具有高度鲁棒性，即使这些速率常数确实影响翻转速率;该特征对于非平衡系统是独特的。
英文摘要：
We present a detailed analysis, based on the Forward Flux Sampling (FFS) simulation method, of the switching dynamics and stability of two models of genetic toggle switches, consisting of two mutually-repressing genes encoding transcription factors (TFs); in one model (the exclusive switch), they mutually exclude each other's binding, while in the other model (general switch) the two transcription factors can bind simultaneously to the shared operator region. We assess the role of two pairs of reactions that influence the stability of these switches: TF-TF homodimerisation and TF-DNA association/dissociation. We factorise the flipping rate k into the product of the probability rho(q*) of finding the system at the dividing surface (separatrix) between the two stable states, and a kinetic prefactor R. In the case of the exclusive switch, the rate of TF-operator binding affects both rho(q*) and R, while the rate of TF dimerisation affects only R. In the case of the general switch both TF-operator binding and TF dimerisation affect k, R and rho(q*). To elucidate this, we analyse the transition state ensemble (TSE). For the exclusive switch, varying the rate of TF-operator binding can drastically change the pathway of switching, while changing the rate of dimerisation changes the switching rate without altering the mechanism. The switching pathways of the general switch are highly robust to changes in the rate constants of both TF-operator and TF-TF binding, even though these rate constants do affect the flipping rate; this feature is unique for non-equilibrium systems.
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