STRUCTURE PREDICTION BY PROTEIN THREADING

我们已经开发了计算机方法来预测蛋白质的三维结构， 通过识别折叠基序来构造。蛋白质的序列是 通过数据库中的替代主干结构进行“线程化”， 与该序列最相容的构象通过以下方法鉴定： 近似自由能计算，使用接触电位。工作 已经集中在两个领域：1）用于快速， “自适应”线程，以及2）构建“核心”折叠的数据库 图案我们发现，序列和结构的最佳比对 可以使用吉布斯采样过程来识别。算法样本 子序列块与无缺口核心的替代性比对 定义折叠主题的元素。可供选择的边界 结构内的核心元素也被采样，使得最优的 可以确定公共核心子结构的定义。这种自适应 折叠生态认知的方法保留了有利的统计数据， 块对齐的特性，但允许识别最佳核心 从近似的起始点，如自动 基于二级结构元素的定义。建立一个数据库 我们已经确定了大螺旋和β链 在蛋白质数据库的结构中。为此，我们有 提出了一种基于α-碳距离匹配的算法 矩阵对范例螺旋和β-阶梯，优化， 对于局部失真和/或坐标不精确是鲁棒的。这一核心 折叠基序数据库已被测试-作为线程的目标 搜索已知的结构，使用自适应线程算法。的 这项研究的意义在于，这些方法可以允许3- 三维建模的序列只有远亲的蛋白质 已知结构，并以这种方式提出关于其机制的假设 行动和功能。

We have developed computer methods to predict protein three-dimensional structure by recognition of folding motif. A protein's sequence is "threaded" through alternative backbone structures in a database, and the conformations most compatible with that sequence are identified by approximate free-energy calculation, using contact potentials. The work has focused on two areas: 1) development of algorithms for fast, "adaptive" threading, and 2) construction of a database of "core" folding motifs. We have found that optimal alignments of a sequence and structure may be identified using a Gibbs Sampling procedure. The algorithm samples alternative alignments of subsequence blocks with the ungapped core elements which define the folding motif. Alternative boundaries of the core elements within the structure are also sampled, so that the optimal definition of common core substructure may be identified. This adaptive approach to fold ecognition preserves the favorable statistical properties of block alignment, yet allows identification of optimal core substructures from an approximate starting point, such as an automatic definition based on secondary structural elements. To build a database of folding motifs we have identified the large helices and beta strands within structures from the protein Data Bank. For this purpose we have developed an algorithm based on matching of alpha-carbon distance matrices against paradigm helices and beta-ladders, optimized to be robust against local distortions and/or coordinate imprecision. This core folding motif database has been tested-as the target for a threading search of known structures, using the adaptive threading algorithm. The significance of this research is that these methods may allow 3- dimensional modeling for sequences only distantly related to proteins of known structure, and in this way suggest hypotheses as to their mechanism of action and function.