Simple, yet powerful methodologies for conformational sampling of proteins
Simple, yet powerful methodologies for conformational sampling of proteins
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DOI：
10.1039/c4cp05262e
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发表时间：
2015-01-01
影响因子：
3.3
通讯作者：
Shigeta, Yasuteru
中科院分区：
文献类型：
--
作者：
Harada, Ryuhei;Takano, Yu;Shigeta, Yasuteru
蛋白质的构象变化与其生物学功能密切相关，如分子识别、酶催化、信号转导、变构调节和蛋白质折叠等。这些构象转变一般诱导为集体运动后的缓慢动力学，包括生物相关的蛋白质的大幅波动。虽然分子动力学（MD）模拟已成为提取蛋白质构象转变的有力工具，但由于MD模拟的时间尺度与生物学时间尺度相差甚远，即使采用大规模并行计算机进行简单的常规MD（CMD）模拟，仍然难以达到生物学功能的时间尺度。因此，需要开发有效的方法来实现具有低计算成本的规范系综。从这个角度出发，我们回顾了我们开发的几种生物分子的增强构象采样技术。在我们的方法中，多个独立的短期MD模拟，而不是单一的简单的长期CMD模拟。我们的基本策略如下：（i）选择初始种子（初始结构）的构象采样重新启动MD模拟。在这里，种子应该被选为具有高转运潜力的候选者。(ii)通过初始化速度重新启动短时MD模拟，从选定的种子中恢复。这些简单方案的循环可能会极大地促进生物分子的构象转变。(iii)一旦从短时间MD模拟的周期中提取的反应性轨迹获得，自由能分布通过伞采样（US）技术与加权直方图分析方法（WHAM）作为后处理技术进行评估。对于初始种子的选择，我们提出了四种不同的选择：（1）并行Cascade分子动力学（PaCS-MD），（2）波动淹没方法（FFM），（3）离群FLOOD（OFLOOD）方法，（4）TaBoo SeArch（TBSA）方法。我们展示了我们的方法的应用程序，几个生物系统，如大幅度波动的蛋白质的结构域运动，配体结合后的构象转变，和蛋白质折叠/重折叠到天然结构的蛋白质。最后，我们展示了我们的方法与CMD模拟和其他先前开发的增强型构象采样方法相比的构象采样效率。
Several biological functions, such as molecular recognition, enzyme catalysis, signal transduction, allosteric regulation, and protein folding, are strongly related to conformational transitions of proteins. These conformational transitions are generally induced as slow dynamics upon collective motions, including biologically relevant large-amplitude fluctuations of proteins. Although molecular dynamics (MD) simulation has become a powerful tool for extracting conformational transitions of proteins, it might still be difficult to reach time scales of the biological functions because the accessible time scales of MD simulations are far from biological time scales, even if straightforward conventional MD (CMD) simulations using massively parallel computers are employed. Thus, it is desirable to develop efficient methods to achieve canonical ensembles with low computational costs. From this perspective, we review several enhanced conformational sampling techniques of biomolecules developed by us. In our methods, multiple independent short-time MD simulations are employed instead of single straightforward long-time CMD simulations. Our basic strategy is as follows: (i) selection of initial seeds (initial structures) for the conformational sampling in restarting MD simulations. Here, the seeds should be selected as candidates with high potential to transit. (ii) Resampling from the selected seeds by initializing velocities in restarting short-time MD simulations. A cycle of these simple protocols might drastically promote the conformational transitions of biomolecules. (iii) Once reactive trajectories extracted from the cycles of short-time MD simulations are obtained, a free energy profile is evaluated by means of umbrella sampling (US) techniques with the weighted histogram analysis method (WHAM) as a post-processing technique. For the selection of the initial seeds, we proposed four different choices: (1) Parallel CaScade molecular dynamics (PaCS-MD), (2) Fluctuation Flooding Method (FFM), (3) Outlier FLOODing (OFLOOD) method, and (4) TaBoo SeArch (TBSA) method. We demonstrate applications of our methods to several biological systems, such as domain motions of proteins with large-amplitude fluctuations, conformational transitions upon ligand binding, and protein folding/refolding to native structures of proteins. Finally, we show the conformational sampling efficiencies of our methods compared with those by CMD simulations and other previously developed enhanced conformational sampling methods.