Theoretical studies of the mechanical unfolding of the muscle protein titin: Bridging the time-scale gap between simulation and experiment
Theoretical studies of the mechanical unfolding of the muscle protein titin: Bridging the time-scale gap between simulation and experiment
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DOI：
10.1063/1.1615233
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发表时间：
2003-11-01
影响因子：
4.4
通讯作者：
Makarov, DE
中科院分区：
文献类型：
--
作者：
Li, PC;Makarov, DE
单分子机械展开实验的蛮力，完全原子模拟是不可行的，因为目前的模拟时间尺度比实验探索的时间尺度短约6个数量级。为了克服这一困难，我们构建了一个模型，其中肌肉蛋白肌联蛋白I27结构域的解折叠动力学被描述为在存在外部驱动势和平均力G（R）的势的情况下沿着单个解折叠坐标R（等于结构域延伸）的扩散运动。剩余自由度的影响用具有摩擦系数η的粘性力来描述。平均力G（R）的势是从用R的约束值执行的一系列平衡分子动力学轨迹计算的，并且η是从一系列转向分子动力学模拟提取的，其中R以恒定速率增加，并且分子的机械响应作为时间的函数被监测。估计的G（R）使我们能够通过过渡态理论计算力依赖的展开速率，并通过进行动力学Monte Carlo模拟来预测实验相关制度中的展开力分布。我们比较了计算的展开自由能分布与推导出的原子力显微镜研究的肌联蛋白，并发现，而在零力展开自由能势垒几乎是相同的实验值，力的依赖性的障碍是非线性的，在对比最唯象模型的肌联蛋白展开。因此，外推到零解折叠力的解折叠速率的值k（u）（0）以及解折叠过渡态的位置不同于先前从实验数据估计的那些。特别是，我们估计的k（u）（0）是几个数量级低于在化学变性实验中测得的解折叠速率，这表明这两种实验技术可能探测不同的解折叠途径。同时，展开力的分布，以及它的依赖于我们的模拟预测的拉动率被发现与原子力显微镜实验。(C)2003年，美国物理学会。
Brute-force, fully atomistic simulations of single molecule mechanical unfolding experiments are not feasible because current simulation time scales are about six orders of magnitude shorter than the time scales explored by experiments. To circumvent this difficulty, we have constructed a model, in which the unfolding dynamics of the I27 domain of the muscle protein titin is described as diffusive motion along a single unfolding coordinate R (equal to the domain extension) in the presence of an external driving potential and the potential of mean force G(R). The effect of the remaining degrees of freedom is described in terms of a viscous force with a friction coefficient eta. The potential of mean force G(R) is computed from a series of equilibrium molecular dynamics trajectories performed with constrained values of R and eta is extracted from a series of steered molecular dynamics simulations, in which R is increased at a constant rate and the mechanical response of the molecule is monitored as a function of time. The estimated G(R) allows us to calculate the force-dependent unfolding rate via transition-state theory and-by performing kinetic Monte Carlo simulations-to predict unfolding force distributions in experimentally relevant regimes. We compare the computed unfolding free energy profile with that deduced from atomic force microscopy studies of titin and find that, while the unfolding free energy barrier at zero force is nearly identical to the experimental value, the force dependence of the barrier is nonlinear, in contrast to most phenomenological models of titin unfolding. Because of this, the value k(u)(0) of the unfolding rate extrapolated to zero unfolding force, as well as the location of the unfolding transition state, differ from those previously estimated from experimental data. In particular, our estimate of k(u)(0) is several orders of magnitude lower than the unfolding rate measured in chemical denaturation experiments, suggesting that the two experimental techniques may probe different unfolding pathways. At the same time, the distribution of the unfolding force as well as its dependence on the pulling rate predicted by our simulations are found to be in agreement with atomic force microscopy experiments. (C) 2003 American Institute of Physics.