Kinetic network study of the diversity and temperature dependence of Trp-Cage folding pathways: combining transition path theory with stochastic simulations.
Kinetic network study of the diversity and temperature dependence of Trp-Cage folding pathways: combining transition path theory with stochastic simulations.
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DOI：
10.1021/jp1089596
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发表时间：
2011-02-17
影响因子：
3.3
通讯作者：
Levy, Ronald M.
中科院分区：
文献类型：
--
作者：
Zheng, Weihua;Gallicchio, Emilio;Deng, Nanjie;Andrec, Michael;Levy, Ronald M.
我们提出了一种新的方法来研究众多的折叠途径和不同的折叠机制的20个残基的迷你蛋白质色氨酸笼使用的复制交换分子动力学（REMD）模拟的构象采样，过渡路径理论（TPT）的组合功率构建折叠途径和随机模拟采样的途径在一个高维的结构空间。采用全原子力场（OPLSAA）和隐式溶剂模型（AGBNP），对Trp笼在270 ~ 566 K温度范围内进行了16个副本的REMD模拟。收集从所有温度取样的构象。它们形成了一个离散化的状态空间，可以用来模拟折叠过程。可以使用加权直方图分析方法（WHAM）计算在目标温度下每个状态的平衡布居。通过连接具有相似结构的状态并创建满足详细平衡条件的边缘，我们构建了一个保持状态空间平衡种群分布的动力学网络。定义折叠和展开宏状态后，通过求解网络中每个节点的一组线性方程来计算提交者概率（Pfold），并使用TPT算法提取路径及其通量。通过将途径聚集成折叠“管”，折叠途径多样性的更有物理意义的图片出现了。随机模拟进行了网络和一个程序的开发项目采样轨迹上的折叠管。由随机轨迹计算的通过折叠管的通量与由TPT分析得到的相应值吻合得很好。研究了Trp-Cage折叠途径系综的温度依赖性。在折叠温度以上，大量具有可比通量的不同折叠路径充斥着能量景观。然而，在低温下，折叠转变仅由几个局部途径主导。
We present a new approach to study a multitude of folding pathways and different folding mechanisms for the 20-residue mini-protein Trp-Cage using the combined power of replica exchange molecular dynamics (REMD) simulations for conformational sampling, Transition Path Theory (TPT) for constructing folding pathways and stochastic simulations for sampling the pathways in a high dimensional structure space. REMD simulations of Trp-Cage with 16 replicas at temperatures between 270K and 566K are carried out with an all-atom force field (OPLSAA) and an implicit solvent model (AGBNP). The conformations sampled from all temperatures are collected. They form a discretized state space that can be used to model the folding process. The equilibrium population for each state at a target temperature can be calculated using the Weighted-Histogram-Analysis Method (WHAM). By connecting states with similar structures and creating edges satisfying detailed balance conditions, we construct a kinetic network that preserves the equilibrium population distribution of the state space. After defining the folded and unfolded macrostates, committor probabilities (Pfold) are calculated by solving a set of linear equations for each node in the network and pathways are extracted together with their fluxes using the TPT algorithm. By clustering the pathways into folding “tubes”, a more physically meaningful picture of the diversity of folding routes emerges. Stochastic simulations are carried out on the network and a procedure is developed to project sampled trajectories onto the folding tubes. The fluxes through the folding tubes calculated from the stochastic trajectories are in good agreement with the corresponding values obtained from the TPT analysis. The temperature dependence of the ensemble of Trp-Cage folding pathways is investigated. Above the folding temperature, a large number of diverse folding pathways with comparable fluxes flood the energy landscape. At low temperature, however, the folding transition is dominated by only a few localized pathways.
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影响因子：
2.9
作者：
Felts, AK;Harano, Y;Levy, RM
通讯作者：
Levy, RM
影响因子：
4.4
作者：
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通讯作者：
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DOI：
10.1073/pnas.0408970102
发表时间：
2005-05-10
影响因子：
11.1
作者：
Andrec, M;Felts, AK;Levy, RM
通讯作者：
Levy, RM
影响因子：
8.6
作者：
Best, RB;Hummer, G
通讯作者：
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影响因子：
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作者：
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通讯作者：
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