Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
J Phys Chem B. 2010 Nov 25;114(46):15227-35. doi: 10.1021/jp1053698. Epub 2010 Oct 22.
We propose a network-based method for determining basins and barriers of complex free energy surfaces (e.g., the protein folding landscape) from the time series of a single intramolecular distance. First, a network of transitions is constructed by clustering the points of the time series according to the short-time distribution of the signal. The transition network, which reflects the short-time kinetics, is then used for the iterative determination of individual basins by the minimum-cut-based free energy profile, a barrier-preserving one-dimensional projection of the free energy surface. The method is tested using the time series of a single C(β)-C(β) distance extracted from equilibrium molecular dynamics (MD) simulations of a structured peptide (20 residue three-stranded antiparallel β-sheet). Although the information of only one distance is employed to describe a system with 645 degrees of freedom, both the native state and the unfolding barrier of about 10 kJ/mol are determined with remarkable accuracy. Moreover, non-native conformers are identified by comparing long-time distributions of the same distance. To examine the applicability to single-molecule Förster resonance energy transfer (FRET) experiments, a time series of donor and acceptor photons is generated using the MD trajectory. The native state of the β-sheet peptide is determined accurately from the emulated FRET signal. Applied to real single-molecule FRET measurements on a monomeric variant of λ-repressor, the network-based method correctly identifies the folded and unfolded populations, which are clearly separated in the minimum-cut-based free energy profile.
我们提出了一种基于网络的方法，用于从单个分子内距离的时间序列中确定复杂自由能表面（例如蛋白质折叠景观）的盆地和障碍。首先，通过根据信号的短时间分布对时间序列中的点进行聚类来构建跃迁网络。然后，将跃迁网络用于通过基于最小割的自由能剖面（自由能表面的一维屏障保留投影）迭代确定单个盆地，该方法通过对具有 645 个自由度的系统进行平衡分子动力学（MD）模拟提取的单个 C（β）-C（β）距离的时间序列进行了测试（β））肽（20 残基三股反平行β-折叠）。尽管仅使用一个距离的信息来描述一个具有 645 个自由度的系统，但以惊人的精度确定了天然状态和约 10 kJ/mol 的展开障碍。此外，通过比较相同距离的长时间分布来识别非天然构象。为了检验其在单分子Förster 共振能量转移（FRET）实验中的适用性，使用 MD 轨迹生成供体和受体光子的时间序列。从模拟的 FRET 信号准确确定了β-折叠肽的天然状态。应用于单体 λ-阻遏物的真实单分子 FRET 测量，基于网络的方法正确识别了折叠和展开的群体，它们在基于最小切割的自由能剖面上明显分开。
