Mezer Aviv, Ashery Uri, Gutman Menachem, Project Elad, Bosis Eran, Fibich Gadi, Nachliel Esther
Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, Tel Aviv University, Israel.
Biochim Biophys Acta. 2006 Apr;1763(4):345-55. doi: 10.1016/j.bbamcr.2006.02.011. Epub 2006 Mar 27.
We have recently created a kinetic model that reproduces the dynamics of exocytosis with high accuracy. The reconstruction necessitated a search, in a multi-dimensional parameter space, for 37 parameters that described the system, with no assurance that the parameters, which reconstructed the observations, are a unique set. In the present study, a Genetic Algorithm (GA) was used for a thorough search in the unknown parameter space, using a strategy of gradual increase of the complexity of the analyzed input data. Upon systematic incorporation of one to four measurable parameters, used as input signals for the analysis, the constraint set on the GA search imposed the convergence of the free parameters into a single narrow range. The mean values for each adjustable parameter represent a minimum for the fitness function in the multi-dimensional parameter space. The GA search demonstrates that the parameters that control the kinetics of exocytosis are the rate constants of the steps downstream to synaptotagmin binding, and that the equilibrium constant of the binding of calcium to Munc13 controls the calcium-dependent priming process. Thus, the systematic use of the GA creates a link between specific reactions in the process of exocytosis and experimental phenotypes.
我们最近创建了一个动力学模型，该模型能够高精度地再现胞吐作用的动力学过程。重建过程需要在多维参数空间中搜索描述该系统的37个参数，而且无法确定能够重建观测结果的参数是否是唯一的一组。在本研究中，我们使用遗传算法（GA）在未知参数空间中进行全面搜索，采用逐步增加分析输入数据复杂度的策略。在系统地纳入一到四个可测量参数作为分析的输入信号后，GA搜索上施加的约束集使自由参数收敛到一个狭窄的范围内。每个可调参数的平均值代表多维参数空间中适应度函数的最小值。GA搜索表明，控制胞吐作用动力学的参数是突触结合蛋白结合下游步骤的速率常数，并且钙与Munc13结合的平衡常数控制着钙依赖性引发过程。因此，GA的系统使用在胞吐作用过程中的特定反应与实验表型之间建立了联系。
