Zheng Weihua, Andrec Michael, Gallicchio Emilio, Levy Ronald M
Department of Physics and Astronomy, Rutgers, The State University of New Jersey, 136 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15340-5. doi: 10.1073/pnas.0704418104. Epub 2007 Sep 18.
Replica exchange (RE) is a generalized ensemble simulation method for accelerating the exploration of free-energy landscapes, which define many challenging problems in computational biophysics, including protein folding and binding. Although temperature RE (T-RE) is a parallel simulation technique whose implementation is relatively straightforward, kinetics and the approach to equilibrium in the T-RE ensemble are very complicated; there is much to learn about how to best employ T-RE to protein folding and binding problems. We have constructed a kinetic network model for RE studies of protein folding and used this reduced model to carry out "simulations of simulations" to analyze how the underlying temperature dependence of the conformational kinetics and the basic parameters of RE (e.g., the number of replicas, the RE rate, and the temperature spacing) all interact to affect the number of folding transitions observed. When protein folding follows anti-Arrhenius kinetics, we observe a speed limit for the number of folding transitions observed at the low temperature of interest, which depends on the maximum of the harmonic mean of the folding and unfolding transition rates at high temperature. The results shown here for the network RE model suggest ways to improve atomic-level RE simulations such as the use of "training" simulations to explore some aspects of the temperature dependence for folding of the atomic-level models before performing RE studies.
复制交换（RE）是一种广义系综模拟方法，用于加速对自由能景观的探索，自由能景观定义了计算生物物理学中的许多具有挑战性的问题，包括蛋白质折叠和结合。尽管温度复制交换（T-RE）是一种并行模拟技术，其实现相对简单，但T-RE系综中的动力学和达到平衡的方法非常复杂；关于如何最好地将T-RE应用于蛋白质折叠和结合问题，还有很多需要学习的地方。我们构建了一个用于蛋白质折叠RE研究的动力学网络模型，并使用这个简化模型进行“模拟的模拟”，以分析构象动力学的潜在温度依赖性和RE的基本参数（例如，副本数量、RE速率和温度间距）如何相互作用来影响观察到的折叠转变数量。当蛋白质折叠遵循反阿仑尼乌斯动力学时，我们在感兴趣的低温下观察到观察到的折叠转变数量存在一个速度限制，这取决于高温下折叠和解折叠转变速率的调和平均值的最大值。这里展示的网络RE模型的结果提出了改进原子水平RE模拟的方法，例如在进行RE研究之前使用“训练”模拟来探索原子水平模型折叠的温度依赖性的某些方面。
