Estimating local backbone structural deviation in homology models
Estimating local backbone structural deviation in homology models
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DOI：
10.1016/s0097-8485(99)00044-3
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发表时间：
2000-01-01
期刊：
影响因子：
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通讯作者：
Abagyan, R
中科院分区：
文献类型：
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作者：
Cardozo, T;Batalov, S;Abagyan, R
在原子坐标本身之后，同源模型中最重要的数据是与每个原子相关的空间可靠性估计（原子注释）。最近的盲同源建模预测表明，基本上正确的序列结构比对可实现低至 25% 的序列同一性[Martin, A.C., MacArthur, M.W., Thornton, J.M., 1997。 CASP2 中比较模型的评估。蛋白质增刊(1), 14-28]。然而，正确对齐的同源蛋白质结构之间的主干空间偏差的位置和程度仍然很难估计，并且这些错误是错误循环预测的原因[Abagyan, R., Batalov, S., Cardozo, T., Totrov, M., Webber, J., Zhou, Y., 1997。具有内部坐标力学变形区域映射的同源建模和模型的改进 构象搜索。蛋白质增刊(1)，29-37]。为了获得局部主链偏差的准确测量，我们对同源蛋白质结构对之间的静态局部主链偏差进行了系统研究。我们发现，除了局部序列同一性之外，“通过空间”接近间隙和链末端、局部三维“密度”、三维环境保持和模板的 B 因子也会导致主干的局部偏差。基于这些发现，我们确定了有意义的值范围，其中每个参数都与静态局部主干偏差相关，并生成了组合评分函数，以极大地改进局部主干偏差的估计。优化后的函数的准确性是局部序列同一性或单独的 B 因子的两倍以上，并在最近的盲结构预测实验中得到了验证。该方法可用于评估初步同源模型对于特定生物学研究（例如药物设计）的效用，或为分子力学环路预测方法提供改进的起点。 (C) 2000 Elsevier Science Ltd. 保留所有权利。
After the atomic coordinates themselves, the most important data in a homology model are the spatial reliability estimates associated with each of the atoms (atom annotation). Recent blind homology modeling predictions have demonstrated that principally correct sequence-structure alignments are achievable to sequence identities as low as 25% [Martin, A.C., MacArthur, M.W., Thornton, J.M., 1997. Assessment of comparative modeling in CASP2. Proteins Suppl(1), 14-28]. The locations and extent of spatial deviations in the backbone between correctly aligned homologous protein structures remained very poorly estimated however, and these errors were the cause of errant loop predictions [Abagyan, R., Batalov, S., Cardozo, T., Totrov, M., Webber, J., Zhou, Y., 1997. Homology modeling with internal coordinate mechanics deformation zone mapping and improvements of models via conformational search. Proteins Suppl(1), 29-37]. In order to derive accurate measures for local backbone deviations, we made a systematic study of static local backbone deviations between homologous pairs of protein structures. We found that 'through space' proximity to gaps and chain termini, local three-dimensional 'density', three-dimensional environment conservation, and B-factor of the template contribute to local deviations in the backbone in addition to local sequence identity. Based on these finding, we have identified the meaningful ranges of values within which each of these parameters correlates with static local backbone deviation and produced a combined scoring function to greatly improve the estimation of local backbone deviations. The optimized function has more than twice the accuracy of local sequence identity or B-factor alone and was validated in a recent blind structure prediction experiment. This method may be used to evaluate the utility of a preliminary homology model for a particular biological investigation (e.g. drug design) or to provide an improved starting point for molecular mechanics loop prediction methods. (C) 2000 Elsevier Science Ltd. All rights reserved.