Amala Arumugam, Emerson Isacc Arnold
School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu. India.
Protein Pept Lett. 2017 Aug;24(6):517-527. doi: 10.2174/0929866524666170413120940.
Depiction of protein structures as networks of interacting residues has enabled us to understand the structure and function of the protein. Previous investigations on closeness centrality have identified protein functional sites from three- dimensional structures. It is well recognized that ligand binding to a receptor protein induces a wide range of structural changes.
An interesting question is how central residues function during conformational changes triggered during ligand binding? The aim of this study is to comprehend at what extent central residues change during ligand binding to receptor proteins.
To determine this, we examined 37 pairs of protein structures consisting of ligand-bound and ligand-free forms. These protein structures were modelled as an undirected network and significant central residues were obtained using residue centrality measures. In addition to these, the basic network parameters were also analysed.
On analysing the residue centrality measures, we observed that 60% of central residues were common in both the ligand-bound and ligand-free states. The geometry of the central residues revealed that they were situated closer to the protein center of the mass. Finally, we demonstrated the effectiveness of central residues in amino acids substitutions and in the evolution itself. The closeness centrality was also analyzed among different protein domain sizes and the values gradually declined from single-domains to multi-domain proteins suggesting that the network has potential for hierarchical organization. Betweenness centrality measure was also used to determine the central residues and 31% of these residues were common between the holo/apo states.
Findings reveal that central residues play a significant role in determining the functional properties of proteins. These results have implications in predicting binding/active site residues, specifically in the context of drug designing, if additional information concerning ligand binding is exploited.
将蛋白质结构描绘为相互作用残基的网络使我们能够理解蛋白质的结构和功能。先前对接近中心性的研究已从三维结构中识别出蛋白质功能位点。众所周知，配体与受体蛋白的结合会引发广泛的结构变化。
一个有趣的问题是，在配体结合引发的构象变化过程中，中心残基是如何发挥作用的？本研究的目的是了解在配体与受体蛋白结合过程中，中心残基在多大程度上发生变化。
为了确定这一点，我们研究了37对由结合配体和未结合配体形式组成的蛋白质结构。这些蛋白质结构被建模为无向网络，并使用残基中心性度量获得重要的中心残基。除此之外，还分析了基本的网络参数。
通过分析残基中心性度量，我们观察到60%的中心残基在结合配体和未结合配体状态下是相同的。中心残基的几何结构表明它们更靠近蛋白质的质心。最后，我们证明了中心残基在氨基酸替换和进化本身中的有效性。还分析了不同蛋白质结构域大小之间的接近中心性，其值从单结构域蛋白到多结构域蛋白逐渐下降，这表明该网络具有层次组织的潜力。还使用中介中心性度量来确定中心残基，其中31%的这些残基在全酶/脱辅基状态之间是相同的。
研究结果表明，中心残基在决定蛋白质的功能特性方面发挥着重要作用。如果利用有关配体结合的额外信息，这些结果在预测结合/活性位点残基方面具有重要意义，特别是在药物设计的背景下。
