Computational mapping identifies the binding sites of organic solvents on proteins
Computational mapping identifies the binding sites of organic solvents on proteins
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DOI：
10.1073/pnas.062398499
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发表时间：
2002-04-02
影响因子：
11.1
通讯作者：
Vajda, S
中科院分区：
文献类型：
--
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
计算映射将分子探针（小分子或功能基团）放置在蛋白质表面，以确定最有利的结合位置。尽管X射线晶体学和NMR显示有机溶剂结合到蛋白质上的有限数量的位点，但目前的映射方法导致数百个能量最小值，并且不能揭示为什么某些位点结合具有不同大小和极性的分子。我们描述了一个映射算法，解释了这种现象的起源。该算法已被应用到鸡蛋白溶菌酶和嗜热菌蛋白酶，相互作用与八个和四个不同的配体，分别。在这两种情况下，搜索都能找到所有分子结合的共有位点，而不一定能找到仅结合某些配体的其他位置。共有位点是活性位点的口袋，排列着部分暴露的疏水残基，边缘有一些极性残基。这些位点可以容纳许多旋转状态的每个配体，其中一些具有与附近的供体/受体基团之一的氢键。特定的底物和/或抑制剂的鸡蛋白溶菌酶和嗜热菌蛋白酶相互作用的映射确定的相同的侧链，但形成几个氢键，并结合在独特的方向。
Computational mapping places molecular probes-small molecules or functional groups-on a protein surface to identify the most favorable binding positions. Although x-ray crystallography and NMR show that organic solvents bind to a limited number of sites on a protein, current mapping methods result in hundreds of energy minima and do not reveal why some sites bind molecules with different sizes and polarities. We describe a mapping algorithm that explains the origin of this phenomenon. The algorithm has been applied to hen egg-white lysozyme and to thermolysin, interacting with eight and four different ligands, respectively. In both cases the search finds the consensus site to which all molecules bind, whereas other positions that bind only certain ligands are not necessarily found. The consensus sites are pockets of the active site, lined with partially exposed hydrophobic residues and with a number of polar residues toward the edge. These sites can accommodate each ligand in a number of rotational states, some with a hydrogen bond to one of the nearby donor;/acceptor groups. Specific substrates and/or inhibitors of hen egg-white lysozyme and thermolysin interact with the same side chains identified by the mapping, but form several hydrogen bonds and bind in unique orientations.