Muff S, Caflisch A
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
J Chem Phys. 2009 Mar 28;130(12):125104. doi: 10.1063/1.3099705.
The rate of protein folding is governed by the transition state so that a detailed characterization of its structure is essential for understanding the folding process. In vitro experiments have provided a coarse-grained description of the folding transition state ensemble (TSE) of small proteins. Atomistic details could be obtained by molecular dynamics (MD) simulations but it is not straightforward to extract the TSE directly from the MD trajectories, even for small peptides. Here, the structures in the TSE are isolated by the cut-based free-energy profile (cFEP) using the network whose nodes and links are configurations sampled by MD and direct transitions among them, respectively. The cFEP is a barrier-preserving projection that does not require arbitrarily chosen progress variables. First, a simple two-dimensional free-energy surface is used to illustrate the successful determination of the TSE by the cFEP approach and to explain the difficulty in defining boundary conditions of the Markov state model for an entropically stabilized free-energy minimum. The cFEP is then used to extract the TSE of a beta-sheet peptide with a complex free-energy surface containing multiple basins and an entropic region. In contrast, Markov state models with boundary conditions defined by projected variables and conventional histogram-based free-energy profiles are not able to identify the TSE of the beta-sheet peptide.
蛋白质折叠的速率由过渡态决定，因此对其结构进行详细表征对于理解折叠过程至关重要。体外实验已经对小蛋白质的折叠过渡态系综（TSE）给出了粗粒度的描述。原子细节可通过分子动力学（MD）模拟获得，但即使对于小肽段，直接从MD轨迹中提取TSE也并非易事。在此，通过基于切割的自由能分布（cFEP），利用其节点和链接分别为由MD采样的构象及其之间的直接转变所构成的网络，来分离TSE中的结构。cFEP是一种保留势垒的投影，不需要任意选择的进展变量。首先，使用一个简单的二维自由能表面来说明通过cFEP方法成功确定TSE，并解释为熵稳定的自由能最小值定义马尔可夫状态模型边界条件时的困难。然后，cFEP被用于提取具有包含多个盆地和一个熵区域的复杂自由能表面的β-折叠肽段的TSE。相比之下，由投影变量定义边界条件的马尔可夫状态模型和传统的基于直方图的自由能分布无法识别β-折叠肽段的TSE。
