PROTEIN THREADING METHODS

我们已经开发了计算机方法来比较 蛋白质序列与结构上的“折叠”文库 数据库。该序列通过可选的结构被“穿线”， 而那些最相容的是通过能量计算来识别的， 使用接触电势。因为它们直接检测到结构 相似性，穿线方法可以识别非常遥远的进化 通过序列比较可能无法检测到的关系。 今年的研究集中在核心元件的测试上 穿线方法，在盲预测和控制实验中，以及 关于提高灵敏度的算法改进。控制 使用已知结构的实验确定了 成功的折叠识别和准确的建模：类似的 “核心”亚结构必须包含60%或更多的蛋白质，并且 必须叠加到2.5埃或更小的残差，以便 很大一部分联系人被保留了下来。对以下方面的预测分析 1996年CASP2讲习班(结构的关键评估 预测)证实了这一结论。结构相似性可以是 然而，在一些远距离关系的情况下，不那么广泛，而且 已经考虑了几项提高灵敏度的改进。 关于数据库结构“核心”的新定义， 在具有已知结构的同系物中可重叠的区域具有 已被证明可以减少线程预测中的假阴性。 接触电势与序列模体得分的组合是 也被证明在困难的识别问题中增加了敏感性。 使用严格的p值计算可以减少错误 积极的一面。有了这些改进，折叠识别可能会 预计将可靠地检测到更大比例的距离 进化关系，一种正在接受测试的可能性 1998年CASP3研讨会的盲目预测。

We have developed computer methods to compare a protein's sequence with a library of "folds" from the structural database. The sequence is "threaded" through alternative structures, and those most compatible are identified by energy calculations, using contact potentials. Since they directly detect structural similarity, threading methods can identify very distant evolutionary relationships that may be undetectable by sequence comparison. Research this year has focused on testing of the core-element threading method, in blind predictions and control experiments, and on algorithmic improvements to increase sensitivity. Control experiments using known structures identified thresholds for successful fold recognition and accurate modeling: the similar "core" substructure must comprise 60% or more of the protein and must superpose to a residual of 2.5 Angstroms or less, such that a large fraction of contacts are preserved. Analysis of predictions for the 1996 CASP2 workshop (Critical Assessment of Structure Prediction) confirmed this conclusion. Structural similarity can be less extensive in some cases of distant relationship, however, and several improvements to increase sensitivity have been considered. New definitions of the "core" of database structures, according to the regions superimposable in homologs with known structures, has been show to reduce false negatives in threading predictions. Combination of contact potentials with sequence-motif scores was also shown to increases sensitivity in difficult recognition problems. Use of rigorous p-value calculations was shown to reduce false positives. With these improvements fold recognition may be expected to reliably detect a greater proportion of the distant evolutionary relationships, a possibility that is being tested with blind predictions for the 1998 CASP3 workshop.