Toward a robust computational screening strategy for identifying glycosaminoglycan sequences that display high specificity for target proteins.
Toward a robust computational screening strategy for identifying glycosaminoglycan sequences that display high specificity for target proteins.
复制标题
制定稳健的计算筛选策略，用于识别对靶蛋白表现出高特异性的糖胺聚糖序列。
DOI：
10.1093/glycob/cwu077
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发表时间：
2014
期刊：
影响因子：
4.3
通讯作者：
Desai,UmeshR
中科院分区：
文献类型：
--
作者：
Sankaranarayanan,NehruViji;Desai,UmeshR
糖胺聚糖 (GAG) 与许多蛋白质相互作用，调节止血、细胞粘附、生长和分化以及病毒感染等过程。然而，大多数这些相互作用在分子水平上仍然知之甚少。造成这种状态的一个主要原因是 GAG 显着的结构多样性，这妨碍了对其相互作用的特异性进行分析。我们之前提出了一种基于组合虚拟库筛选 (CVLS) 技术预测“高特异性”GAG 序列的计算协议。在这项工作中，我们通过严格研究影响 GAG 识别蛋白质（尤其是抗凝血酶和凝血酶）的参数来扩展该技术的稳健性。 CVLS 方法涉及自动构建所有可能的寡糖序列（二糖至八糖）的虚拟库，然后采用由“亲和力”（GOLD 评分）和“特异性”（结合一致性）过滤器组成的两步选择策略。我们发现，使用 100 次遗传算法实验、100,000 次进化和从 10 Å（二糖）到 14 Å（六糖）的可变对接半径，可以对“特异性”特征进行最佳评估。结果强调了 H/HS 寡糖中控制特异性的关键相互作用。将CVLS技术应用于抗凝血酶-肝素系统表明最小的“特异性”元素是肝素的GlcAp(1→4)GlcNp2S3S二糖。 CVLS 技术为设计较长的 GAG 序列提供了一个简单、直观的框架，该序列可以表现出高“特异性”，而无需对数百万个理论序列进行详尽的筛选。
Glycosaminoglycans (GAGs) interact with many proteins to regulate processes such as hemostasis, cell adhesion, growth and differentiation and viral infection. Yet, majority of these interactions remain poorly understood at a molecular level. A major reason for this state is the phenomenal structural diversity of GAGs, which has precluded analysis of specificity of their interactions. We had earlier presented a computational protocol for predicting “high-specificity” GAG sequences based on combinatorial virtual library screening (CVLS) technology. In this work, we expand the robustness of this technology through rigorous studies of parameters affecting GAG recognition of proteins, especially antithrombin and thrombin. The CVLS approach involves automated construction of a virtual library of all possible oligosaccharide sequences (di- to octasaccharide) followed by a two-step selection strategy consisting of “affinity” (GOLD score) and “specificity” (consistency of binding) filters. We find that “specificity” features are optimally evaluated using 100 genetic algorithm experiments, 100,000 evolutions and variable docking radius from 10 Å (disaccharide) to 14 Å (hexasaccharide). The results highlight critical interactions in H/HS oligosaccharides that govern specificity. Application of CVLS technology to the antithrombin–heparin system indicates that the minimal “specificity” element is the GlcAp(1 → 4)GlcNp2S3S disaccharide of heparin. The CVLS technology affords a simple, intuitive framework for the design of longer GAG sequences that can exhibit high “specificity” without resorting to exhaustive screening of millions of theoretical sequences.