Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, United States.
J Struct Biol. 2013 Oct;184(1):75-82. doi: 10.1016/j.jsb.2013.05.020. Epub 2013 Jun 13.
Distance constraints, in principle, can be employed to determine information about the location of probes within a three-dimensional volume. Traditional methods for locating probes from distance constraints involve optimization of scoring functions that measure how well the probe location fits the distance data, exploring only a small subset of the scoring function landscape in the process. These methods are not guaranteed to find the global optimum and provide no means to relate the identified optimum to all other optima in scoring space. Here, we introduce a method for the location of probes from distance information that is based on probability calculus. This method allows exploration of the entire scoring space by directly combining probability functions representing the distance data and information about attachment sites. The approach is guaranteed to identify the global optimum and enables the derivation of confidence intervals for the probe location as well as statistical quantification of ambiguities. We apply the method to determine the location of a fluorescence probe using distances derived by FRET and show that the resulting location matches that independently derived by electron microscopy.
距离约束原则上可用于确定探针在三维体积内的位置信息。从距离约束确定探针位置的传统方法涉及评分函数的优化，该评分函数用于衡量探针位置与距离数据的拟合程度，在此过程中仅探索评分函数景观的一小部分。这些方法不能保证找到全局最优解，也无法将确定的最优解与评分空间中的所有其他最优解联系起来。在这里，我们介绍了一种基于概率论的从距离信息中确定探针位置的方法。该方法允许通过直接组合表示距离数据和附着位点信息的概率函数来探索整个评分空间。该方法保证能够识别全局最优解，并能够为探针位置导出置信区间，以及对不确定性进行统计量化。我们应用该方法来确定荧光探针的位置，该位置是通过 FRET 得到的距离来确定的，并表明得到的位置与通过电子显微镜独立得到的位置相匹配。
