Protein-ligand interactions: probing the energetics of a putative cation-π interaction.
Protein-ligand interactions: probing the energetics of a putative cation-π interaction.
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DOI：
10.1016/j.bmcl.2014.04.114
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发表时间：
2014-07-15
影响因子：
2.7
通讯作者：
Martin, Stephen F.
中科院分区：
文献类型：
--
作者：
Myslinski, James M.;Clements, John H.;Martin, Stephen F.
关键词：
为了探测与推定的阳离子-π相互作用相关的能量学，确定Grb 2 SH 2结构域与RCO-pTyr-Ac 6c-Asn的三肽衍生物之间的复合物形成的热力学参数，其中R基团变化以包括不同的烷基、环烷基和芳基。尽管吲哚环被认为与胍离子离子具有最强的相互作用，但带有环己基和苯基的RCO-pTyr-Ac 6c-Asn衍生物的结合自由能ΔG°略优于其吲哚类似物。两个复合物的晶体学分析表明，测试配体结合在类似的姿势与显着的例外的相对取向和接近的苯基和吲哚环相对于精氨酸残基的域。这些空间取向与在其他阳离子-π相互作用中观察到的一致，但在该生物系统中，这种相互作用没有净能量效益。因此，尽管阳离子-π相互作用被充分证明是分子识别中重要的非共价力，但这种相互作用的能量学可以通过蛋白质-配体缔合中的其他非键合相互作用和溶剂化效应来减轻。
In order to probe the energetics associated with a putative cation-π interaction, thermodynamic parameters are determined for complex formation between the Grb2 SH2 domain and tripeptide derivatives of RCO–pTyr–Ac6c–Asn wherein the R group is varied to include different alkyl, cycloalkyl, and aryl groups. Although an indole ring is reputed to have the strongest interaction with a guanidinium ion ion, binding free energies, ΔG°, for derivatives of RCO–pTyr–Ac6c–Asn bearing cyclohexyl and phenyl groups were slightly more favorable than their indolyl analog. Crystallographic analysis of two complexes reveals that test ligands bind in similar poses with the notable exception of the relative orientation and proximity of the phenyl and indolyl rings relative to an arginine residue of the domain. These spatial orientations are consistent with those observed in other cation-π interactions, but there is no net energetic benefit to such an interaction in this biological system. Accordingly, although cation-π interactions are well documented as important noncovalent forces in molecular recognition, the energetics of such interactions may be mitigated by other nonbonded interactions and solvation effects in protein-ligand associations.
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