Combinatorial docking approach for structure prediction of large proteins and multi-molecular assemblies
Combinatorial docking approach for structure prediction of large proteins and multi-molecular assemblies
复制标题
DOI：
10.1088/1478-3975/2/4/s10
复制
发表时间：
2005-12-01
期刊：
影响因子：
2
通讯作者：
Wolfson, HJ
中科院分区：
文献类型：
--
作者：
Inbar, Y;Benyamini, H;Wolfson, HJ
蛋白质折叠和蛋白质结合是类似的过程。在这两种情况下，结构单元相互结合。在折叠的情况下，我们主要处理共价连接的相对较小的单元，构建块或结构域。在多分子结合的情况下，亚基相对较大并且仅通过非共价键缔合。在实验上，确定这种大型组件的结构的难度随着其包含的复杂尺寸和部件数量而增加。在计算上，多分子复合物结构的预测在很大程度上还没有得到解决，可能是由于该问题的组合复杂性的大小。目前的对接算法主要针对预测成对相互作用。在这里，我们的目标是预测多单元关联的结构，无论这些是蛋白质折叠中的链连接，还是组装中分离的不相交分子。我们假设单个单元的结构是已知的，无论是通过实验测定或建模。我们的目标是组合组装这些单元来预测它们的结构。为了解决这个问题，我们开发了CombDock。CombDock是一种解决结构单元装配问题的组合对接算法。下面，我们简要地描述了算法，并提出了它的各种应用程序的例子折叠和多分子组装。为了测试算法的鲁棒性，我们使用不准确的结构单元模型，这些模型来自未结合分子的晶体结构或靶序列的建模。该算法已经能够预测近本地的安排，在几乎所有的情况下，输入的结构单元，这表明组合的方法可以克服不完美的形状互补性所造成的模型的不准确性。此外，我们进一步表明，通过组合对接策略，它是可能的，以提高参与多分子组装的成对相互作用的预测。
Protein folding and protein binding are similar processes. In both, structural units combinatorially associate with each other. In the case of folding, we mostly handle relatively small units, building blocks or domains, that are covalently linked. In the case of multi-molecular binding, the subunits are relatively large and are associated only by non-covalent bonds. Experimentally, the difficulty in the determination of the structures of such large assemblies increases with the complex size and the number of components it contains. Computationally, the prediction of the structures of multi-molecular complexes has largely not been addressed, probably owing to the magnitude of the combinatorial complexity of the problem. Current docking algorithms mostly target prediction of pairwise interactions. Here our goal is to predict the structures of multi-unit associations, whether these are chain-connected as in protein folding, or separate disjoint molecules in the assemblies. We assume that the structures of the single units are known, either through experimental determination or modeling. Our aim is to combinatorially assemble these units to predict their structure. To address this problem we have developed CombDock. CombDock is a combinatorial docking algorithm for the structural units assembly problem. Below, we briefly describe the algorithm and present examples of its various applications to folding and to multi-molecular assemblies. To test the robustness of the algorithm, we use inaccurate models of the structural units, derived either from crystal structures of unbound molecules or from modeling of the target sequences. The algorithm has been able to predict near-native arrangements of the input structural units in almost all of the cases, suggesting that a combinatorial approach can overcome the imperfect shape complementarity caused by the inaccuracy of the models. In addition, we further show that through a combinatorial docking strategy it is possible to enhance the predictions of pairwise interactions involved in a multi-molecular assembly.