STRUCTURE PREDICTION BY PROTEIN THREADING

我们已经开发出计算机方法来预测蛋白质的三维结构 通过识别结构数据库中类似的“折叠”来识别结构。 蛋白质的序列通过不同的构象“串连”在一起，并且 最相容的是用近似自由能来识别的 使用接触电势进行计算。研究集中在三个方面 领域：1)用新的序列测试穿线方法，2) 开发用于预测的可信度统计，以及3)开发 改善了接触电势。“自适应”线程算法， 基于块对齐和Gibb抽样优化，在 Asilomar研讨会关于这一主题的盲目预测实验。 在两个预测中的两个中，未知被准确地表示出来 在我们的“核心”数据库中，正确的模型被确定为 TOP 3，具有准确的序列-结构比对。在另外两个 预测测试统计数据显示信心不佳，而这些蛋白质 事实证明，与已知褶皱的相似性较小，不准确 在核心数据库中显示。为这些开发的测试统计数据 预测实验是基于Shuffed的分数分布 序列，这是一种允许我们严格纠正因 序列组成和比对空间大小。预测 实验还表明，潜力和核心的适度改善 定义将被证明是重要的，因为一些预测略低于 信心门槛。出于这个原因，我们已经开始开发 基于更详细的接触对表示的新势 几何学，以及更精确的保守核心子结构的定义。 这项研究的意义在于，它可能会允许三维 仅与已知蛋白质有远缘关系的序列的建模 结构，从而提出了关于其作用机制的假设 和功能。我们对肥胖基因产物的线索预测， 例如，表明与遗传性肥胖有关的瘦素 在结构上和可能在功能上类似于螺旋细胞因子。

We have developed computer methods to predict protein three-dimensional structure by recognition of similar "folds" in the structural database. A protein's sequence is "threaded" through alternative conformations, and those most compatible are identified by approximate free-energy calculation, using contact potentials. Research has focussed in three areas: 1) testing of the threading method with novel sequences, 2) development of confidence statistics for predictions, and 3) development of improved contact potentials. The "adaptive" threading algorithm, based on block alignment and Gibb's sampling optimization, was tested in blind prediction experiments for the Asilomar workshop on this topic. In two of two predictions where the unknown was accurately represented in our "core" database, the correct model was identified as one of the top 3, with accurate sequence-structure alignment. In two other predictions test statistics indicated poor confidence, and these proteins proved to have less extensive similarity to known folds, not accurately represented in the core database. Test statistics developed for these prediction experiments were based on score distributions for shuffled sequences, a procedure which allow us to rigorously correct for bias due to sequence composition and alignment -space size. Prediction experiments also suggested that modest improvement in potentials and core definition will prove important, since some predictions were just below the confidence threshold. For this reason we have begun development of new potentials, based on more detailed representation of contact-pair geometry, and more precise definitions of conserved core substructure. The significance of this research is that it may allow 3-dimensional modeling for sequences only distantly related to proteins of known structure, and thus suggest hypotheses as to their mechanism of action and function. Our threading prediction for the Obese gene product, for example, has suggested that leptin, implicated in hereditary obesity, is structurally and perhaps functionally similar to the helical cytokines.