Fundamentals of Ligand-Protein Interactions

小分子配体及其蛋白质结合部位(在许多情况下是酶的催化活性部位)的配对的构象变化是许多药物作用的中心方面，也是药物设计计算方法中的一个关键挑战。在该领域最早的出版物之一中，WE“http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed和Cmd=ShowDetailView和TermToSearch=8581425和OrdialPos=47和itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum”表明，对于蛋白质数据库和剑桥结构数据库中都存在的一小组配体，柔性化合物通常不会以其全局真空能量构象与蛋白质结合，并且经常甚至在任何局部真空能量构象中也不结合。虽然这项研究使用了当时可用的最大数据集和最佳方法，但自那以来，实验数据库中的结构数量以及可用的软件和硬件资源都呈指数级增长。因此，我们正在重新讨论这个重要的话题，对数量级的分析，更多的结构，以及在计算量子化学理论的高水平上执行的计算。在这个项目到目前为止取得的其他里程碑中，我们已经提取了最近在PDB的“http://ligand-expo.rcsb.org/”LigandEXPO“中提供的所有小分子配体的出现。截至2008年5月，这是一组超过350,000组不同的3D坐标。我们添加了来自几个不同来源的大量注释。在过滤器链中使用这些注释，我们已经生成了高质量和高可靠性的配体结构的“高质量”子集，根据应用的严格程度，从大约1000次到大约5000次不等。我们对这些高质量配体的构象能进行了高水平的量子化学计算。在第一轮中，真空能量计算部分在我们自己的LINUX集群上运行，部分在美国国立卫生研究院CIT的“http://biowulf.nih.gov/”Biowulf集群“上运行。在这个计算量巨大的项目中，同时使用了多达1000个CPU，单个作业需要几个小时到几个星期的CPU时间。我们从大约360次成功完成的运行中获得了结果。这些结果清楚地表明，这些量子化学计算充分证实了高构象能的可能性。在2008年10月13日至17日在费城布林莫尔举行的“http://echeminfo.com/COMTY_conferencesprog08”eCheminfo2008年互动会议上，在马克·尼克劳斯主持的关于“http://echeminfo.com/comty_confprog08pdbligands”PDB配体：分析其结构和结合数据的会议上作了介绍。由于在本届会议上对这些问题进行了讨论，一个由“关切的科学家”组成的国际小组聚集在一起，称为Ligand Quality Working Group，它将试图通过非正式和更有条理的合作以及信息的自由流动，试图至少更集中地关注这一情况，如果不是以各种方式改善它的话。为了探索水环境对配体构象能的可能影响-毕竟，真空并不是药物分子通常操作的地方-进行了第二轮量子化学计算，使用了Gauss03中的SCI-PCM溶剂模型。与真空计算相比，这些运行对计算机资源的要求更高。为了分析能量不确定性作为位置不确定性的函数，而位置不确定性又是结晶学分辨率的函数，我们在分子力学力场水平上以晶体结构构象为中心进行了构象采样，得到了依赖于分辨率的扭转分布。目前正在将所有这些成果综合在一起，并撰写成关于这一主题的一系列主要出版物。

The conformational changes of both partners of a ligand-protein complex, the small-molecule ligand its the protein binding site (in many cases the catalytically active site of an enzyme) are a central aspect many drug actions, as well as a crucial challenge in computational approaches to drug design. In one of the earliest publications in the this field, we "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed and Cmd=ShowDetailView and TermToSearch=8581425 and ordinalpos=47 and itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" showed for a small set of ligands occurring both in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) that flexible compounds are not usually bound to a protein in their global vacuum energy conformation, and oftentime not even in any local vacuum energy conformation. While this study used the largest set of data and best methodology available at that time, both the number of structures in either experimental database and the software and hardware resource available have since grown exponentially. We are thus revisiting this important topic with an analysis of orders of magnitudes more structures, and computations performed at a high level of computational quantum-chemical theory. Among other milestones achieved so far in this project, we have extracted all occurrences of small-molecule ligands recently made available in PDB's "http://ligand-expo.rcsb.org/" LigandExpo. As of May 2008, this is a set of over 350,000 distinct sets of 3D coordinates. We have added extensive annotation coming from several different sources. Using these annotations in a chain of filters, we have generated "high-quality" subsets of ligand structures of high quality and reliability numbering from just about one thousand to about 5,000 occurrences depending on the stringency applied. We have conducted high-level quantum-chemical calculations of conformational energies for these high-quality ligand sets. In the first round, vacuum energy calculations were run partly on our own Linux cluster, partly on the "http://biowulf.nih.gov/" Biowulf cluster of the CIT, NIH. Up to a thousand CPUs were used simultaneously in this computationally massive project, with individual jobs taking from a few hours to several weeks of CPU-time. We obtained results from about 360 runs that completed successfully. These results clearly showed that the possibility for high conformational energies are fully confirmed by these quantum-chemical calculations. They were presented at the "http://echeminfo.com/COMTY_conferencesprog08" eCheminfo 2008 InterAction Meeting at Bryn Mawr, Philadelphia (13-17 October 2008) in the session on "http://echeminfo.com/comty_confprog08pdbligands" PDB Ligands: Analysing their Structure and Binding Data, chaired by Marc Nicklaus. As a result of the discussions about these issues at this session, an international group of "concerned scientists" has come together, called the Ligand Quality Working Group, which will attempt, in collaborations both informal and more structured, and by free flow of information, to attempt to at least shine a more focused light on this situation, if not improve it in various ways. To explore the possible influence of aqueous environment on ligand conformational energies - after all, vacuum is not really where drug molecules typically operate - a second round of quantum chemical calculations was conducted, employing the SCI-PCM solvent model in Gaussian 03. These runs were even more demanding in terms of computer resources than the vacuum calculations. To analyze the energetic uncertainty as a function of the positional uncertainty, which in turn is a function of the crystallographic resolution, we conducted sampling of conformations with a resolution-dependent torsion distribution centered around the crystal structure conformation at the molecular mechanics force field level. All these results are currently being combined and written up in a series of major publications on this topic.