On the diversity of physicochemical environments experienced by identical ligands in binding pockets of unrelated proteins
On the diversity of physicochemical environments experienced by identical ligands in binding pockets of unrelated proteins
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DOI：
10.1002/prot.22633
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发表时间：
2010-04-01
影响因子：
2.9
通讯作者：
Thornton, Janet M.
中科院分区：
文献类型：
--
作者：
Kahraman, Abdullah;Morris, Richard J.;Thornton, Janet M.
大多数从结合位点分析鉴定同源配体的功能预测方法基于分子互补性的假设。这些方法建立在配体和结合位点之间的几何和物理化学性质的互补性的基础上，使得相似的结合位点将结合相似的配体。我们发现，这种假设通常不适用于蛋白质-配体相互作用，并观察到，它不是配体分子的化学组成决定蛋白质和配体分子之间的互补性，但配体在蛋白质的功能机制中的份额决定了互补性的程度。在这里，我们提出了一套同源配体的描述性分析和比较的物理化学性质，每个配体的经验，在各种非同源结合口袋。在每个配体集的比较揭示了他们的经验丰富的物理化学性质的变化很大，这表明相同的配体可以结合到不同的物理化学环境。在一些蛋白质配体复合物中，发现这种变化与配体分子的电化学特性相关，而在另一些蛋白质中，它被公开为蛋白质生化功能的先决条件。为了实现结合，观察到蛋白质参与静电和疏水相互作用之间的微妙平衡行为，以产生稳定的结合自由能。对于所提出的分析，一个新的方法得分从分子环境的疏水性与实验确定的去溶剂化能量显示出高度的相关性。所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微妙之处的方法方面所面临的挑战。
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.