The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.
The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.
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DOI：
10.1038/nprot.2015.043
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发表时间：
2015-05
期刊：
影响因子：
14.8
通讯作者：
Vajda S
中科院分区：
文献类型：
--
作者：
Kozakov D;Grove LE;Hall DR;Bohnuud T;Mottarella SE;Luo L;Xia B;Beglov D;Vajda S
FTMap是一种计算映射服务器，可识别大分子的结合热点，即，区域的表面主要贡献的配体结合自由能。要使用FTMap，用户需要提交PDB格式的蛋白质、DNA或RNA结构。FTMap对数十亿个用作探针的小有机分子的位置进行采样，并使用详细的能量表达式对探针姿势进行评分。结合多种探针类型的簇的区域识别结合热点，与实验数据良好一致。FTMap作为其他服务器的基础，即预测配体结合位点的FTSite，考虑侧链灵活性的FTFlex，参数化附加探针的FTMap/param，以及映射蛋白质结构集合的FTDyn。其应用包括确定蛋白质的可药用性，鉴定对结合最重要的配体部分，在未配体的蛋白质结构的集合中找到最类似结合的构象，以及为基于片段的药物设计提供输入。FTMap比经典的作图方法如GRID和MCSS更准确，并且比基于混合分子动力学的蛋白质作图方法更快。使用16个探针分子，FTMap服务器在不到一小时的时间内找到了平均大小蛋白质的热点。由于FTFlex对结合位点侧链的所有低能构象异构体进行映射，因此其完成时间相应较长。
FTMap is a computational mapping server that identifies binding hot spots of macromolecules, i.e., regions of the surface with major contributions to the ligand binding free energy. To use FTMap, users submit a protein, DNA, or RNA structure in PDB format. FTMap samples billions of positions of small organic molecules used as probes and scores the probe poses using a detailed energy expression. Regions that bind clusters of multiple probe types identify the binding hot spots, in good agreement with experimental data. FTMap serves as basis for other servers, namely FTSite to predict ligand binding sites, FTFlex to account for side chain flexibility, FTMap/param to parameterize additional probes, and FTDyn to map ensembles of protein structures. Applications include determining druggability of proteins, identifying ligand moieties that are most important for binding, finding the most bound-like conformation in ensembles of unliganded protein structures, and providing input for fragment based drug design. FTMap is more accurate than classical mapping methods such as GRID and MCSS, and is much faster than the more recent approaches to protein mapping based on mixed molecular dynamics. Using 16 probe molecules, the FTMap server finds the hot spots of an average size protein in less than an hour. Since FTFlex performs mapping for all low energy conformers of side chains in the binding site, its completion time is proportionately longer.