A solvated ligand rotamer approach and its application in computational protein design
A solvated ligand rotamer approach and its application in computational protein design
复制标题
溶剂化配体旋转异构体方法及其在计算蛋白质设计中的应用
DOI：
10.1007/s00894-012-1695-6
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发表时间：
2013-03-01
影响因子：
2.2
通讯作者：
Zhu, Yushan
中科院分区：
文献类型：
--
作者：
Huang, Xiaoqiang;Yang, Ji;Zhu, Yushan
基于结构设计不同小分子的蛋白质-配体界面对于发现功能蛋白具有重要意义。通过对一组蛋白质-配体复合物结构的统计分析，确定了水介导的蛋白质-配体界面氢键对蛋白质与配体的结合起着至关重要的调控作用。基于新的统计结果，我们提出了一种溶剂化配体旋转体方法来明确描述蛋白质-配体界面上的关键水分子，并将水介导的氢键模型应用于计算蛋白质设计中，以补充连续介质溶剂模型。溶剂化配体旋转体方法对配体旋转体库中的每个旋转体只产生一个额外的溶剂化旋转体，并且不会改变每个蛋白质设计位点侧链旋转体的数量。这大大减少了蛋白质设计中序列选择的总组合数，并通过两次试验验证了模型的准确性。对于水放置测试，在五种蛋白质-配体复合物结构中，61%的晶体水分子被正确预测。对于序列重述测试，使用溶剂化配体旋转体方法和水介导氢键模型恢复了44.7%的氨基酸身份，而当去除显结合水时，仅恢复了30.4%的氨基酸身份。这些结果表明，所开发的溶剂化配体旋转体方法有望用于针对新型蛋白质-配体相互作用的功能蛋白设计。
The structure-based design of protein-ligand interfaces with respect to different small molecules is of great significance in the discovery of functional proteins. By statistical analysis of a set of protein-ligand complex structures, it was determined that water-mediated hydrogen bonding at the protein-ligand interface plays a crucial role in governing the binding between the protein and the ligand. Based on the novel statistic results, a solvated ligand rotamer approach was developed to explicitly describe the key water molecules at the protein-ligand interface and a water-mediated hydrogen bonding model was applied in the computational protein design context to complement the continuum solvent model. The solvated ligand rotamer approach produces only one additional solvated rotamer for each rotamer in the ligand rotamer library and does not change the number of side-chain rotamers at each protein design site. This has greatly reduced the total combinatorial number in sequence selection for protein design, and the accuracy of the model was confirmed by two tests. For the water placement test, 61 % of the crystal water molecules were predicted correctly in five protein-ligand complex structures. For the sequence recapitulation test, 44.7 % of the amino acid identities were recovered using the solvated ligand rotamer approach and the water-mediated hydrogen bonding model, while only 30.4 % were recovered when the explicitly bound waters were removed. These results indicated that the developed solvated ligand rotamer approach is promising for functional protein design targeting novel protein-ligand interactions.