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，蛋白质结构的很大一部分将是精度有限的模型。因此，构建该网络的基于结构的方法必须(a)快速，(b)对建模结构的显着不准确性不敏感。这些方法的精度可能与蛋白质结构的精度有关，在较不精确的模型中较低，在较精确的模型中较高。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结合来建立。本提案的主题是基于结构的研究方法的发展。长期目标是了解蛋白质相互作用的基本原理，并创建基于结构的全基因组描述，重点是基于结构的蛋白质途径建模，蛋白质相互作用动力学和动力学的准确描述，具有特殊性质的蛋白质结构工程，以及基于模型结构的计算机辅助药物设计。具体目标为：(1)对接建模蛋白结构；(2)结合位点预测与比较；(3)预测相互作用蛋白与非相互作用蛋白；(4)开发蛋白质相互作用建模的公共资源。蛋白质-蛋白质复合物数据库（包括不同精度的模型）和蛋白质对接诱饵数据库将用于开发对接和结合位点预测方法和精度改进程序。分子间能量景观特征将用于识别相互作用的蛋白质。数据集和程序将成为建模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.