DESIGN AND TESTING OF DOCKING ALGORITHMS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的长期目标是解决“对接问题”，即预测蛋白质-配体复合体的结构和配体特性。这样做的方法将在结构功能研究中得到广泛应用。具体目标是： 1.开发在几何和化学复杂性不断增加的层次中对接配体的算法。 虽然配体-蛋白质复合体的构型空间很大，但它也是高度冗余的，并且受到复合体排除体积的限制。作为状态集合的对接分子允许利用这些特征的方法。通过以越来越复杂的层次表示分子，有可能在计算的早期排除最不利的构象。这种分层算法应该适用于相关的化学，就像适用于相关构象一样。这些方法将探索比现在对接计算中所能考虑的更多的状态和化学。对溶剂化能模型的改进也将被研究。 2.在性能良好的实验系统上对新算法进行测试。 新的算法将测试它们预测两个模型系统的新配体和几何结构的能力：AmpCβ-内酰胺酶和溶菌酶中的空穴位置。这两种蛋白质都很容易处理，并为对接研究提供了明确的位置。在最简单的层面上，实验测试将通过结构确定来评估算法的“命中率”及其准确性。更根本的是，这将有助于研究复杂地层中的热力学驱动力。 大量的初步结果表明，新算法是可行的。例如，请参阅以下文章： A.使用构象系综进行灵活的配体对接 B.按家族对接分子以增加数据库屏幕中点击的多样性 C.具有多个配体残基构象和多个残基同一性的蛋白质-蛋白质对接 该模型系统似乎非常适合测试新算法。例如，请参阅以下文章： A.热点区域AmpC酶活性部位的定位 B.基于结构发现一种新的非共价AmpC酶抑制剂 C.分子对接中用于测试评分功能的模型结合位点 通过RBVI提供的交互式计算机图形是可视化和评估对接计算执行情况的关键，也是基于结构发现新配体的关键。它们对晶体建模和结构确定也非常有用，这是该项目实验测试方面的一部分。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long term goal is to address the "docking problem," that of predicting the structures and ligand identities of protein-ligand complexes. Methods to do so would have wide application in structure-function studies. The specific aims are: 1. To develop algorithms that dock ligands in hierarchies of increasing geometrical and chemical complexity. Although the configuration space for ligand-protein complexes is enormous, it is also highly redundant and constrained by the excluded volume of the complex. Docking molecules as ensembles of states allow for methods that take advantage of these features. By representing molecules in hierarchies of increasing complexity, it may be possible to exclude most unfavorable conformations early in the calculation. Such a hierarchical algorithm should be applicable to related chemistries in the same way as to related conformations. These methods would explore many more states and chemistries than can now be considered in docking calculations. Improvements to solvation energy models will also be investigated. 2. To test the new algorithms in a well-behaved experimental system. The new algorithms will be tested for their ability to predict new ligands and geometries for two model systems: AmpC beta-lactamase and a cavity site in lysozyme. Both proteins are easy to work with and provide well defined sites for docking studies. At the simplest level, the experimental tests will evaluate "hit-rates" for the algorithms and their accuracy through structure determination. More fundamentally, this will alllow for investigation of the thermodynamic driving forces in complex formation. Extensive prelimary results suggest that the new algorithms are feasible. See the following articles for instance: a. Flexible Ligand Docking Using Conformational Ensembles b. Docking Molecules by Families to Increase the Diversity of Hits in Database Screens c. Protein-Protein Docking with Multiple Ligand Residue Conformations and Multiple Residue Identities The model system seems to be well suited to testing the new algorithms. See the following articles for instance: a. Mapping the Active Site of AmpC beta-Lactamase for Hot Spots b. Structure-based Discovery of a Novel, Non-Covalent Inhibitor of AmpC beta-Lactamase c. A Model Binding Site for Testing Scoring Functions in Molecular Docking Interactive computer graphics available through the RBVI are key to visualizing and evaluating how well docking calculations have performed, and to the structure-based discovery of new ligands. They are also very useful for crystallographic modeling and structure determination, which is part of the experimental testing aspect of this project.