Comparative protein structure modeling by iterative alignment, model building and model assessment
Comparative protein structure modeling by iterative alignment, model building and model assessment
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DOI：
10.1093/nar/gkg460
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发表时间：
2003-07-15
影响因子：
14.9
通讯作者：
Sali, A
中科院分区：
文献类型：
--
作者：
John, B;Sali, A
比较蛋白质结构建模或同源蛋白质结构建模受到建模序列与已知三维结构的相关蛋白质比对错误的严重限制。为改善这一问题，我们开发了一种自动化方法，可同时优化比对及其所隐含的模型。这一任务通过一种遗传算法协议实现，该协议从一组初始比对开始，然后通过重新比对、模型构建和模型评估进行迭代，以优化模型评估分数。在这个迭代过程中：（i）通过应用一些操作符（如比对突变和交叉）构建新的比对；（ii）通过满足空间限制来构建与这些比对相对应的比较模型，这在我们的程序MODELLER中得以实现；（iii）通过多种标准对模型进行评估，部分取决于原子统计势能。当在一组非常困难的19个建模目标上测试该程序时，这些目标与其模板结构仅具有4 - 27%的序列同一性，相对于初始比对，最终比对的平均准确率从37%提高到45%（比对准确率是通过测试比对中与基于参考结构的比对相同的位置百分比来衡量的）。相应地，模型的平均准确率从43%提高到54%（模型准确率是通过模型中在叠加的天然结构中相应的Cα原子的5埃范围内的Cα原子百分比来衡量的）。本方法与之前描述的两种最成功的方法PSI - BLAST和SAM相比也具有优势。如果有更好的模型排序方法，最终模型的准确性将进一步提高。
Comparative or homology protein structure modeling is severely limited by errors in the alignment of a modeled sequence with related proteins of known three-dimensional structure. To ameliorate this problem, we have developed an automated method that optimizes both the alignment and the model implied by it. This task is achieved by a genetic algorithm protocol that starts with a set of initial alignments and then iterates through re-alignment, model building and model assessment to optimize a model assessment score. During this iterative process: (i) new alignments are constructed by application of a number of operators, such as alignment mutations and cross-overs; (ii) comparative models corresponding to these alignments are built by satisfaction of spatial restraints, as implemented in our program MODELLER; (iii) the models are assessed by a variety of criteria, partly depending on an atomic statistical potential. When testing the procedure on a very difficult set of 19 modeling targets sharing only 4-27% sequence identity with their template structures, the average final alignment accuracy increased from 37 to 45% relative to the initial alignment (the alignment accuracy was measured as the percentage of positions in the tested alignment that were identical to the reference structure-based alignment). Correspondingly, the average model accuracy increased from 43 to 54% (the model accuracy was measured as the percentage of the Calpha atoms of the model that were within 5 Angstrom of the corresponding Calpha atoms in the superposed native structure). The present method also compares favorably with two of the most successful previously described methods, PSI-BLAST and SAM. The accuracy of the final models would be increased further if a better method for ranking of the models were available.