Computational Mapping of Proteins for Binding of Ligands

除了提供的空间，计算溶剂映射方法将分子探针-小分子或官能团-放置在蛋白质表面上，以确定最有利的结合位置。X射线晶体学和核磁共振表明，具有不同大小和极性的有机溶剂聚集在蛋白质上有限数量的位点上。最近开发的映射算法可靠地识别不同探针分子结合的共识位点。这些网站是在良好的协议与现有的实验数据。一个非常重要的结果是，酶中的共有位点是底物结合位点的主要亚位点，与探针相互作用的氨基酸残基也结合酶的特异性配体（底物、抑制剂和过渡态类似物）。因此，计算映射可用于功能位点的鉴定和表征。该方法是不太敏感的蛋白质结构的变化比对接方法，是非常强大的算法和能量参数的变化。该提案的目标包括开发高通量自动映射的软件，通过映射一些很好理解的酶来验证该方法，并将该方法应用于尽可能多的表征较差的酶。预计这些结果将提供大量关于酶结合位点的新信息，至少应该建议哪些残基应该通过定点突变实验进行研究。还将测试溶剂图谱识别其他类型蛋白质中功能位点的能力。可靠的作图方法将是特别有用的，因为结构基因组学方法可能产生越来越多的表征不佳的蛋白质的结构，并且很少有基于蛋白质结构识别功能位点的计算方法。在第二种应用中，氨基酸将用作探针，并且将研究单个氨基酸残基的有利结合位置与它们在结合肽中的实际位置之间的关系。性能现场=

EXCEED THE SPACE PROVIDED, Computational solvent mapping methods place molecular probes - small molecules or functional groups - on a protein surface in order to identify the most favorable binding positions. X-ray crystallography and NMR show that organic solvents with different sizes and polarities cluster at a limited number of sites on a protein. A recently developed mapping algorithm reliably identifies the consensus sites at which different probe molecules bind. These sites are in good agreement with the available experimental data. A very important result is that the consensus sites in enzymes are major subsites of the substrate binding site, and the amino acid residues that interact with the probes also bind the specific ligands (substrates, inhibitors, and transition state analogs) of the enzyme. Thus, computational mapping can be used for the identification and characterization of functional sites. The approach is less sensitive to variations in the structure of the protein than docking methods, and is remarkably robust against changes in the algorithm and energy parameters. The goals of this proposal include the development of software for high-throughput automatic mapping, validation of the approach by the mapping of a number of well understood enzymes, and application of the method to as many poorly characterized enzymes as possible. The results are expected to provide a substantial body of new information on enzyme binding sites, and at the very least should suggest which residues should be studied by site-directed mutation experiments. Solvent mapping will also be tested for its ability to identify functional sites in other types of proteins. A reliable mapping method will be particularly useful, as structural genomics approaches are likely to produce structures for an increasing number of poorly characterized proteins, and there are very few computational methods for identifying functional sites on the basis of protein structure, ha a second application, amino acids will be used as probes, and the relationship between favorable binding positions of individual amino acid residues and their actual positions in bound peptides will be studied. PERFORMANCE SITE ========================================Section End===========================================