Maximum likelihood estimation of molecular motor kinetics from staircase dwell-time sequences
Maximum likelihood estimation of molecular motor kinetics from staircase dwell-time sequences
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DOI：
10.1529/biophysj.105.079541
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发表时间：
2006-08-15
影响因子：
3.4
通讯作者：
Sachs, Frederick
中科院分区：
文献类型：
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作者：
Milescu, Lorin S.;Yildiz, Ahmet;Sachs, Frederick
分子马达，如运动蛋白、肌凝蛋白或动力蛋白，通过水解ATP将化学能转化为机械能。机械能用于沿着细胞骨架以离散的步骤移动并携带分子负荷。运动步骤的高分辨率单分子记录显示为一个随机的住宅序列，类似于楼梯。阶梯数据也可以从其他分子机器，如f -1 atp酶，RNA聚合酶，或拓扑异构酶获得。我们开发了一种最大似然算法来估计蛋白质不同构象状态之间的速率常数，包括运动步骤。我们用一个周期马尔可夫模型来模拟电机，该模型反映了电机步骤的重复化学反应。我们通过离散时间马尔可夫模型的似然函数的数值最大化，从理想的驻留序列估计动力学。这种方法消除了遗漏事件纠正的需要。该算法可以拟合任意复杂的动力学模型，如均匀或交替步骤化学、可逆或不可逆动力学、ATP浓度和机械力依赖率等。该方法允许跨平稳和非平稳实验条件的全局拟合，以及用户定义的速率常数的先验约束。用仿真数据对算法进行了验证，并在免费的QuB软件中实现。
Molecular motors, such as kinesin, myosin, or dynein, convert chemical energy into mechanical energy by hydrolyzing ATP. The mechanical energy is used for moving in discrete steps along the cytoskeleton and carrying a molecular load. High resolution single molecule recordings of motor steps appear as a stochastic sequence of dwells, resembling a staircase. Staircase data can also be obtained from other molecular machines such as F-1-ATPase, RNA polymerase, or topoisomerase. We developed a maximum likelihood algorithm that estimates the rate constants between different conformational states of the protein, including motor steps. We model the motor with a periodic Markov model that reflects the repetitive chemistry of the motor step. We estimated the kinetics from the idealized dwell-sequence by numerical maximization of the likelihood function for discrete-time Markov models. This approach eliminates the need for missed event correction. The algorithm can fit kinetic models of arbitrary complexity, such as uniform or alternating step chemistry, reversible or irreversible kinetics, ATP concentration and mechanical force-dependent rates, etc. The method allows global fitting across stationary and nonstationary experimental conditions, and user-defined a priori constraints on rate constants. The algorithm was tested with simulated data, and implemented in the free QuB software.