European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, United Kingdom.
Proteins. 2010 Apr;78(5):1120-36. doi: 10.1002/prot.22633.
Most function prediction methods that identify cognate ligands from binding site analyses work on the assumption of molecular complementarity. These approaches build on the conjectured complementarity of geometrical and physicochemical properties between ligands and binding sites so that similar binding sites will bind similar ligands. We found that this assumption does not generally hold for protein-ligand interactions and observed that it is not the chemical composition of ligand molecules that dictates the complementarity between protein and ligand molecules, but that the ligand's share within the functional mechanism of a protein determines the degree of complementarity. Here, we present for a set of cognate ligands a descriptive analysis and comparison of the physicochemical properties that each ligand experiences in various nonhomologous binding pockets. The comparisons in each ligand set reveal large variations in their experienced physicochemical properties, suggesting that the same ligand can bind to distinct physicochemical environments. In some protein ligand complexes, the variation was found to correlate with the electrochemical characteristic of ligand molecules, whereas in others it was disclosed as a prerequisite for the biochemical function of the protein. To achieve binding, proteins were observed to engage in subtle balancing acts between electrostatic and hydrophobic interactions to generate stabilizing free energies of binding. For the presented analysis, a new method for scoring hydrophobicity from molecular environments was developed showing high correlations with experimental determined desolvation energies. The presented results highlight the complexities of molecular recognition and underline the challenges of computational structural biology in developing methods to detect these important subtleties.
大多数通过结合位点分析识别同源配体的功能预测方法都基于分子互补性的假设。这些方法基于配体和结合位点之间几何形状和物理化学性质的推测互补性，因此相似的结合位点将结合相似的配体。我们发现，这种假设并不普遍适用于蛋白质-配体相互作用，并且观察到不是配体分子的化学成分决定了蛋白质和配体分子之间的互补性，而是配体在蛋白质功能机制中的份额决定了互补性的程度。在这里，我们为一组同源配体提供了对每个配体在各种非同源结合口袋中经历的物理化学性质的描述性分析和比较。在每个配体集中的比较揭示了它们经历的物理化学性质的巨大差异，这表明相同的配体可以结合到不同的物理化学环境中。在一些蛋白质-配体复合物中，这种变化与配体分子的电化学特性相关，而在其他复合物中，这种变化则揭示了蛋白质生化功能的先决条件。为了实现结合，蛋白质被观察到在静电和疏水性相互作用之间进行微妙的平衡，以产生稳定的结合自由能。为了进行这种分析，开发了一种从分子环境中评分疏水性的新方法，该方法与实验测定的去溶剂化能显示出高度相关性。呈现的结果突出了分子识别的复杂性，并强调了计算结构生物学在开发检测这些重要细微差别的方法方面的挑战。
