Stockwell Gareth R, Thornton Janet M
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
J Mol Biol. 2006 Mar 3;356(4):928-44. doi: 10.1016/j.jmb.2005.12.012. Epub 2005 Dec 20.
The phenomenon of molecular recognition, which underpins almost all biological processes, is dynamic, complex and subtle. Establishing an interaction between a pair of molecules involves mutual structural rearrangements guided by a highly convoluted energy landscape, the accurate mapping of which continues to elude us. Increased understanding of the degree to which the conformational space of a ligand is restricted upon binding may have important implications for docking studies, structure refinement and for function prediction methods based on geometrical comparisons of ligands or their binding sites. Here, we present an analysis of the conformational variability exhibited by three of the most ubiquitous biological ligands in nature, ATP, NAD and FAD. First, we demonstrate qualitatively that these ligands bind to proteins in widely varying conformations, including several cases in which parts of the molecule assume energetically unfavourable orientations. Next, by comparing the distribution of bound ligand shapes with the set of all possible molecular conformations, we provide a quantitative assessment of previous observations that ligands tend to unfold when binding to proteins. We show that, while extended forms of ligands are indeed common in ligand-protein structures, instances of ligands in almost maximally compact arrangements can also be found. Thirdly, we compare the conformational variation in two sets of ligand molecules, those bound to homologous proteins, and those bound to unrelated proteins. Although most superfamilies bind ligands in a fairly conserved manner, we find several cases in which significant variation in ligand configuration is observed.
分子识别现象几乎支撑着所有生物过程，它具有动态性、复杂性和微妙性。一对分子之间建立相互作用涉及到由高度复杂的能量景观引导的相互结构重排，而对其精确映射仍让我们难以捉摸。对配体构象空间在结合时受到限制程度的进一步理解，可能对对接研究、结构优化以及基于配体或其结合位点几何比较的功能预测方法具有重要意义。在此，我们对自然界中三种最普遍存在的生物配体ATP、NAD和FAD所表现出的构象变异性进行了分析。首先，我们定性地证明这些配体以广泛不同的构象与蛋白质结合，包括分子的某些部分呈现能量上不利取向的几种情况。接下来，通过将结合配体形状的分布与所有可能分子构象的集合进行比较，我们对先前观察到的配体在与蛋白质结合时倾向于展开的现象进行了定量评估。我们表明，虽然配体的伸展形式在配体 - 蛋白质结构中确实很常见，但也能发现几乎处于最大紧凑排列的配体实例。第三，我们比较了两组配体分子的构象变化，一组是与同源蛋白质结合的，另一组是与不相关蛋白质结合的。尽管大多数超家族以相当保守的方式结合配体，但我们发现了几个观察到配体构型有显著变化的例子。
