DOCKING IN LARGE DATABASES OF MODELED PROTEINS

该项目的主要目标是设计基于结构的程序，以建立基因组中蛋白质之间的连接网络。基因组中蛋白质-蛋白质相互作用的数量明显大于单个蛋白质的数量。此外，很大一部分蛋白质结构将是精度有限的模型。因此，用于构建该网络的基于结构的方法必须(A)快速，并且(B)对建模结构的显著不准确性不敏感。这些方法的精度可能与蛋白质结构的精度有关，对于不太精确的模型，精度较低，而对于较精确的模型，精度较高。蛋白质之间的连接网络必须通过实验研究、基于知识的数据、序列分析和结构方法的组合来建立。这项提议的主题是基于结构的研究的方法论发展。长期目标是了解蛋白质相互作用的基本原理，并建立基于结构的整个基因组的描述，重点是基于结构的蛋白质途径建模，准确描述蛋白质相互作用的动力学和动力学，具有特殊性质的蛋白质结构的工程，以及基于建模结构的计算机辅助药物设计。其具体目标是：(1)模拟蛋白质结构的对接，(2)结合位点的预测和比较，(3)相互作用和非相互作用蛋白质的预测，以及(4)蛋白质相互作用模拟的公共资源的开发。将利用包括不同精度模型的蛋白质-蛋白质复合体数据库和蛋白质对接诱饵数据库来制定对接和结合部位预测方法以及提高准确性的程序。分子间能量景观特征将被用来识别相互作用的蛋白质。这些数据集和程序将成为模拟蛋白质相互作用的公共资源的一部分。

The major goal of the project is to design structure-based procedures for building a network of connections between proteins in genomes. The number of protein-protein interactions in a genome is significantly larger than the number of individual proteins. Moreover, a large part of protein structures will be models of limited accuracy. Thus, the structure-based methods for building this network have to be (a) fast, and (b) insensitive to significant inaccuracies of modeled structures. The precision of these methods may be correlated with the precision of the protein structures lower for less accurate models and higher for more exact models. The networks of connections between proteins have to be built by a combination of experimental studies, knowledge-based data, sequence analysis, and structural approaches. The subject of this proposal is the methodology development for the structure-based studies. The long-term goals are to understand the fundamental principles of protein interaction and to create a structure-based description of entire genomes, with the focus on structure-based modeling of protein pathways, accurate description of dynamics and kinetics of protein interactions, engineering of protein structures with special properties, and computer-aided drug design on modeled structures. The specific aims are: (1) docking of modeled protein structures, (2) binding site prediction and comparison, (3) prediction of interacting and noninteracting proteins, and (4) development of the public resource for modeling protein interactions. The database of protein-protein complexes, that includes models of different accuracy, and the database of protein docking decoys will be used to develop docking and binding site prediction approaches and the accuracy improvement procedures. The intermolecular energy landscape characteristics will be used to identify interacting proteins. The datasets and procedures will become part of the public resource for modeling protein interactions.