从单分子X射线散射中从头确定结构系综：一种贝叶斯方法
De novo structural ensemble determination from single-molecule X-ray scattering: A Bayesian approach
AI总结：
本文提出一种贝叶斯方法，利用自由电子激光单分子X射线散射数据从噪声极低的图像中同时确定生物分子的整个结构系综，并通过合成数据验证其能以较少图像解析多个构象，为“分子电影”奠定基础。
摘要：
利用自由电子激光进行的单分子X射线散射实验为生物分子的结构测定开辟了一条新途径。由于通常每张散射图像只记录极少的光子，因此在这种极端泊松条件下信噪比非常低，结构精修相当具有挑战性。此外，在每次散射事件中，生物分子的取向是随机且未知的。作为另一层复杂性，许多生物分子表现出结构异质性和不同构象之间的构象转变；这些结构动力学被现有的精修方法平均掉了。为了克服这些局限性，我们在此开发并测试了一种严格的贝叶斯方法，并证明通过这些实验不仅能够确定单一结构，而且能够确定整个结构系综。使用由分子动力学轨迹生成的10^6张合成散射图像，我们的方法能够在2 Å分辨率下分辨出八个丙氨酸二肽构象异构体的系综；类似地，我们使用1.2×10^7张图像在4-7 Å分辨率下确定了蛋白质chignolin的去折叠系综。出乎意料的是，确定一个由n个结构组成、每个结构含m个原子的系综所需的图像数量，远少于确定一个含n×m个原子（即总自由度数相同）的单一结构所需的图像数量。这些发现表明，使用最先进的自由电子激光进行X射线散射实验，不仅能够确定生物分子结构，而且能够确定整个结构系综，并最终实现“分子电影”。
英文摘要：
Single molecule X-ray scattering experiments with free electron lasers have opened a new route to the structure determination of biomolecules. Because typically only very few photons per scattering image are recorded and thus the signal-to-noise ratio is very low in this extreme Poisson regime, structure refinement is quite challenging. In addition, in each scattering event the orientation of the biomolecule is random and unknown. As a further layer of complexity, many biomolecules show structural heterogeneity and conformational transitions between different distinct structures; these structural dynamics are averaged out by existing refinement methods. To overcome these limitations, here we developed and tested a rigorous Bayesian approach and demonstrate that it should be possible to determine not only a single structure, but an entire structural ensemble from these experiments. Using $10^6$ synthetic scattering images generated from molecular dynamics trajectories, our approach was able to resolve ensembles of eight alanine dipeptide conformers at $2\,$Å resolution; similarly, we determined the unfolded ensemble of the protein chignolin at $4-7\,$Å resolution using $1.2\cdot 10^7$ images. Unexpectedly, much fewer images are required to determine an ensemble of $n$ structures of $m$ atoms each than a single structure of $n\times m$ atoms, i.e., of the same total number of degrees of freedom. These findings show that X-ray scattering experiments using state-of-the-art free electron lasers should allow one to determine not only biomolecular structures, but whole structure ensembles and, ultimately, 'molecular movies'.
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