Development and Evaluation of GlycanDock: A Protein-Glycoligand Docking Refinement Algorithm in Rosetta.
Development and Evaluation of GlycanDock: A Protein-Glycoligand Docking Refinement Algorithm in Rosetta.
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DOI：
10.1021/acs.jpcb.1c00910
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发表时间：
2021-06-16
期刊：
影响因子：
--
通讯作者：
Gray JJ
中科院分区：
文献类型：
--
作者：
Nance ML;Labonte JW;Adolf-Bryfogle J;Gray JJ
碳水化合物链在生命的复杂分子过程中无处不在。这些高度多样化的链被各种蛋白质受体识别，使聚糖能够调节许多生物功能。蛋白质-糖配体复合物的高分辨率结构揭示了理解这种分子识别水平所必需的原子细节，并为以应用为重点的科学和工程追求提供信息。当实验挑战阻碍高通量测定质量结构时，计算工具原则上可以填补差距。在这项工作中，我们介绍了GlycanDock-一个残基为中心的蛋白质糖配体对接细化算法内的Rosetta大分子建模和设计软件套件。我们使用一组109个实验确定的蛋白质-糖配体复合物以及62个未结合的蛋白质结构进行基准对接评估。GlycanDock算法可以从糖配体环原子中最高达7个均方根偏差的起始结构中采样和区分具有统计可靠性的天然结构准确性的蛋白质-糖配体模型。我们表明，GlycanDock精炼模型定性复制了已知的细菌碳水化合物结合模块的结合特异性。最后，我们提出了一个蛋白质-糖配体对接管道产生推定的蛋白质-糖配体复合物时，只有糖配体序列和未结合的蛋白质结构是已知的。结合其他碳水化合物建模工具，GlycanDock对接细化算法将加速糖科学的研究。
Carbohydrate chains are ubiquitous in the complex molecular processes of life. These highly diverse chains are recognized by a variety of protein receptors, enabling glycans to regulate many biological functions. High-resolution structures of protein–glycoligand complexes reveal the atomic details necessary to understand this level of molecular recognition and inform application-focused scientific and engineering pursuits. When experimental challenges hinder high-throughput determination of quality structures, computational tools can, in principle, fill the gap. In this work, we introduce GlycanDock—a residue-centric protein–glycoligand docking refinement algorithm developed within the Rosetta macromolecular modeling and design software suite. We performed a benchmark docking assessment using a set of 109 experimentally determined protein–glycoligand complexes as well as 62 unbound protein structures. The GlycanDock algorithm can sample and discriminate protein–glycoligand models of native-like structural accuracy with statistical reliability from starting structures of up to 7 Å root-mean-square deviation in the glycoligand ring atoms. We show that GlycanDock-refined models qualitatively replicated the known binding specificity of a bacterial carbohydrate-binding module. Finally, we present a protein–glycoligand docking pipeline for generating putative protein–glycoligand complexes when only the glycoligand sequence and unbound protein structure are known. In combination with other carbohydrate modeling tools, the GlycanDock docking refinement algorithm will accelerate research in the glycosciences.
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