E.大肠杆菌葡萄糖-半乳糖结合蛋白的高采样半原子模拟研究
Thermal Motions of the E. Coli Glucose-Galactose Binding Protein Studied Using Well-Sampled Semi-Atomistic Simulations
摘要：
急诊大肠杆菌葡萄糖-半乳糖化学感受受体（glucose-galactose chemosensory receptor，GCL）是一个309个残基、32 kDa的蛋白质，由两个不同的结构域组成。在这项计算研究中，我们研究了蛋白质的热波动，包括大规模的域间运动，有助于受体的作用机制，以及较小规模的运动，使用两种不同的计算方法。我们采用非常快的，“半原子”基于库的蒙特卡罗（LBMC）模拟，其中包括所有的骨干原子，但“隐式”侧链。我们的结果与以前的实验和全原子Langevin动力学模拟进行了比较。使用载脂蛋白和葡萄糖结合形式的蛋白质进行LBMC和朗之万动力学模拟，LBMC表现出明显更大的波动。LBMC模拟也与Careaga和Falke的二硫化物捕获实验大体一致（JMB，1992; Biophys. J.，1992），这表明晶体结构中的远距离残基（即，β碳相隔10至20埃）在溶液中形成自发的瞬时接触。我们的模拟说明了这些波动的几种可能的“机制”（构型途径）。我们还观察到我们的计算和实验之间的一些差异。尽管如此，我们相信我们的半原子方法可以用于研究其他蛋白质的波动，也许是用于系综对接，或者在虚拟筛选研究中对蛋白质灵活性的其他分析。
英文摘要：
The E. coli glucose-galactose chemosensory receptor is a 309 residue, 32 kDa protein consisting of two distinct structural domains. In this computational study, we studied the protein's thermal fluctuations, including both the large scale interdomain movements that contribute to the receptor's mechanism of action, as well as smaller scale motions, using two different computational methods. We employ extremely fast, "semi-atomistic" Library-Based Monte Carlo (LBMC) simulations, which include all backbone atoms but "implicit" side chains. Our results were compared with previous experiments and an all-atom Langevin dynamics simulation. Both LBMC and Langevin dynamics simulations were performed using both the apo and glucose-bound form of the protein, with LBMC exhibiting significantly larger fluctuations. The LBMC simulations are also in general agreement with the disulfide trapping experiments of Careaga & Falke (JMB, 1992; Biophys. J., 1992), which indicate that distant residues in the crystal structure (i.e. beta carbons separated by 10 to 20 angstroms) form spontaneous transient contacts in solution. Our simulations illustrate several possible "mechanisms" (configurational pathways) for these fluctuations. We also observe several discrepancies between our calculations and experiment. Nevertheless, we believe that our semi-atomistic approach could be used to study the fluctuations in other proteins, perhaps for ensemble docking, or other analyses of protein flexibility in virtual screening studies.
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