PROTEIN DOCKING AND COMPLEMENTARITY
PROTEIN DOCKING AND COMPLEMENTARITY
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DOI：
10.1016/0022-2836(91)80222-g
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发表时间：
1991-09-05
影响因子：
5.6
通讯作者：
KUNTZ, ID
中科院分区：
文献类型：
--
作者：
SHOICHET, BK;KUNTZ, ID
由于这些结构的拓扑和热力学复杂性，预测蛋白质-蛋白质复合物的结构是一个难题。过去在该领域的努力主要集中在使用刚体搜索将相互作用的蛋白质组装在一起，通常使用晶体结构复合物中蛋白质的构象。在这里，我们展示的工作使用刚体对接方法，利用相互作用分子的结合和非结合构象来生成三种已知蛋白质复合物的结构。在所有情况下，我们都可以以高精度重新生成晶体复合物的几何形状。我们还能够找到与晶体结构不相似的几何形状，但在机械上和一些简单的物理标准上却令人惊讶地合理。与该领域之前的工作相比，我们发现评估蛋白质-蛋白质界面互补性的简单方法无法区分类似于晶体结构复合物的构型和不相似的构型。无法区分这种相似和不相似构型的方法包括表面积掩埋、溶剂化自由能、堆积和基于机制的过滤。配合物的总相互作用能和静电相互作用能的评价稍好一些。在我们尝试的技术中，能量最小化最清楚地区分了“真”和“假”阳性，尽管即使在这里能量差异也非常小。我们发现，在所有通过对接产生的假定复合物中，最低的总相互作用能始终在晶体结构的 5Å 均方根范围内。然而，有几种推定的配合物与晶体结构非常不同，但能量却接近低能结构。大分子系统中能量计算误差的大小尚未确定，因此能量微小差异的可靠性仍有待确定。这种对接方法能够利用未结合的构象重新生成相互作用蛋白质的晶体构型，这表明它将成为预测未溶解复合物结构的有用工具。
Predicting the structures of protein-protein complexes is a difficult problem owing to the topographical and thermodynamic complexity of these structures. Past efforts in this area have focussed on fitting the interacting proteins together using rigid body searches, usually with the conformations of the proteins as they occur in crystal structure complexes. Here we present work which uses a rigid body docking method to generate the structures of three known protein complexes, using both the bound and unbound conformations of the interacting molecules. In all cases we can regenerate the geometry of the crystal complexes to high accuracy. We also are able to find geometries that do not resemble the crystal structure but nevertheless are surprisingly reasonable both mechanistically and by some simple physical criteria. In contrast to previous work in this area, we find that simple methods for evaluating the complementarity at the protein-protein interface cannot distinguish between the configurations that resemble the crystal structure complex and those that do not. Methods that could not distinguish between such similar and dissimilar configurations include surface area burial, solvation free energy, packing and mechanism-based filtering. Evaluations of the total interaction energy and the electrostatic interaction energy of the complexes were somewhat better. Of the techniques that we tried, energy minimization distinguished most clearly between the “true” and “false” positives, though even here the energy differences were surprisingly small. We found the lowest total interaction energy from amongst all of the putative complexes generated by docking was always within 5Åroot-mean-square of the crystallographic structure. There were, however, several putative complexes that were very dissimilar to the crystallographic structure but had energies that were close to that of the low energy structure. The magnitude of the error in energy calculations has not been established in macromolecular systems, and thus the reliability of the small differences in energy remains to be determined. The ability of this docking method to regenerate the crystallographic configurations of the interacting proteins using their unbound conformations suggests that it will be a useful tool in predicting the structures of unsolved complexes.