PROTEIN THREADING METHODS

蛋白质穿线方法

• 批准号: 6162796
• 负责人: S H BRYANT
• 金额: --
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162796
• 关键词: chemical information system; chemical models; computer assisted sequence analysis; computer program /software; computer simulation; computer system design /evaluation; conformation; model design /development; protein folding; protein sequence; protein structure; protein structure function; statistics /biometry; thermodynamics

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 Gibbs sampling threading method, in blind predictions and control experiments, and on algorithmic improvements to increase sensitivity. A notable success in blind prediction was the identification of human leptin as a member of the helical cytokine family, published prior experimental verification. 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 sequence, and must superpose to a residual of 2.5 Angstroms or less, such that contact patterns are preserved. Structural similarity can be less extensive in some cases of distant relationship, however, and several improvements to increase sensitivity have been considered. A modified contact potential adding local-structure information has been shown to produce improved threading alignments. 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. Changes in the Gibbs sampling alignment algorithm itself, to detect local minima and test for convergence, have improved the accuracy of statistical significance calculations. 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 1996 Asilomar workshop.

我们开发了计算机方法来比较蛋白质的 具有来自结构的“折叠”文库的序列 数据库该序列是“线程”通过替代 结构，而那些最兼容的是由 能量计算，使用接触电势。因为它们 直接检测结构相似性，线程方法 可以识别非常遥远的进化关系， 可能无法通过序列比较检测到。 研究这个 一年的重点是测试吉布斯采样线程 方法，在盲目的预测和控制实验，和 改进算法以提高灵敏度一 在盲预测中取得的显著成功是 人瘦素作为螺旋细胞因子家族的一员， 发表了先前的实验验证。控制 实验，使用已知的结构，确定阈值 为了成功地进行褶皱识别和精确建模， 类似的“核心”子结构必须包括60%或更多的 序列，并且必须叠加到2.5的残差 角度或更小，使得接触图案 保存。结构相似性可能不太广泛， 然而，有些情况下关系疏远， 已经考虑了提高灵敏度的改进。 一种加入局部结构的改进接触电位 信息已经显示出产生改进的线程 对齐。数据库“核心”的新定义 结构，根据可重叠的区域， 具有已知结构同系物，已显示减少 线程预测中的假阴性。变化 吉布斯采样对齐算法本身，检测局部 最小值和收敛性检验，提高了精度 统计显著性计算。 与这些 折叠识别的改进可能会可靠地 检测到更大比例的遥远进化 关系，一种正在测试的可能性， 1996年阿西洛马研讨会的盲目预测。