Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction.
Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction.
复制标题
抗体结构，结合同源性建模，基于能量的改进和环路预测的组合。
DOI：
10.1002/prot.24551
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发表时间：
2014-08
期刊：
影响因子：
2.9
通讯作者：
Pearlman D
中科院分区：
文献类型：
--
作者：
Zhu K;Day T;Warshaviak D;Murrett C;Friesner R;Pearlman D
我们使用 BioLuminate 和 Prime 程序中实施的全自动抗体结构预测方法，在第二次抗体建模评估 (AMA-II) 中展示了盲法预测结果。我们开发了一种新颖的基于知识的方法来对 CDR 循环进行建模，该方法结合使用序列相似性、几何匹配和数据库结构的聚类。同源模型通过基于物理的能量函数（VSGB2.0）进一步优化，显着提高了模型质量。 H3 循环建模仍然是最具挑战性的任务。我们的从头算环预测对于晶体结构背景下的 H3 环表现良好，并且在同源模型背景下细化 H3 环时可以改进结果。对于本次评估中的 10 种人类和小鼠衍生抗体，同源模型 Fv 和框架区的平均 RMSD 分别为 1.19 Å 和 0.74 Å。五个非 H3 CDR 环的平均 RMSD 范围为 0.61 Å 至 1.05 Å，使用我们基于知识的环预测方法，H3 环平均 RMSD 为 2.91 Å。从头开始 H3 环预测在晶体结构的背景下产生的平均 RMSD 为 1.28 Å，在同源模型结构的背景下产生的平均 RMSD 为 2.67 Å。值得注意的是，我们在晶体结构环境中预测 H3 环的方法在 AMA-II 的七个参赛组中排名第一，并且我们的方法对 10 个目标中的 7 个目标做出了所有参与者中最好的预测。
We present the blinded prediction results in the Second Antibody Modeling Assessment (AMA-II) using a fully automatic antibody structure prediction method implemented in the programs BioLuminate and Prime. We have developed a novel knowledge based approach to model the CDR loops, using a combination of sequence similarity, geometry matching, and the clustering of database structures. The homology models are further optimized with a physics-based energy function (VSGB2.0), which improves the model quality significantly. H3 loop modeling remains the most challenging task. Our ab initio loop prediction performs well for the H3 loop in the crystal structure context, and allows improved results when refining the H3 loops in the context of homology models. For the 10 human and mouse derived antibodies in this assessment, the average RMSDs for the homology model Fv and framework regions are 1.19 Å and 0.74 Å, respectively. The average RMSDs for five non-H3 CDR loops range from 0.61 Å to 1.05 Å, and the H3 loop average RMSD is 2.91 Å using our knowledge-based loop prediction approach. The ab initio H3 loop predictions yield an average RMSD of 1.28 Å when performed in the context of the crystal structure and 2.67 Å in the context of the homology modeled structure. Notably, our method for predicting the H3 loop in the crystal structure environment ranked first among the seven participating groups in AMA-II, and our method made the best prediction among all participants for seven of the ten targets.