Thermodynamic and Structural Effects of Macrocyclic Constraints in Protein-Ligand Interactions
Thermodynamic and Structural Effects of Macrocyclic Constraints in Protein-Ligand Interactions
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DOI：
10.1021/ml100142y
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发表时间：
2010-11-01
影响因子：
4.2
通讯作者：
Martin, Stephen F.
中科院分区：
文献类型：
--
作者：
DeLorbe, John E.;Clements, John H.;Martin, Stephen F.
使用等温滴定量热法和 X 射线晶体学研究了大环化作为稳定 Grb2 SH2 结合肽的生物活性构象的策略的热力学和结构效应，含有序列 pYVN 的 23 元大环比其线性对照稍微更有效，但是预组织不一定会产生更有利的结合 熵，大环 7 及其无环控制 8 的配合物结构相似，除了 7 和 8 的喜欢部分中相应原子的相对方向不同之外。直接或水介导的蛋白质-配体接触的数量没有差异，这可能是 7 不太有利的结合焓的原因，然而，8 中 pY 和 pY+3 残基之间的分子内氢键不存在 7 可能是一个因素。这些研究强调了将蛋白质-配体相互作用中的能量学和结构相关联的困难。
The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and X-ray crystallography, 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls however, preorganization did not necessarily eventuate in a more favorable binding entropy, Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the liking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein-ligand contacts that might account for the less favorable binding enthalpy of 7, however, and intramolecular hydrogen bond between the pY and the pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein-ligand interactions.