Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.
Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.
复制标题
蛋白质-配体相互作用：与增加烷基链长度相关的热力学效应。
DOI：
10.1021/ml400211q
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发表时间：
2013
影响因子：
4.2
通讯作者：
Martin,StephenF
中科院分区：
文献类型：
--
作者：
Myslinski,JamesM;Clements,JohnH;Delorbe,JohnE;Martin,StephenF
测定了Grb2SH2结构域与一般形式的Ac-pTyr-Xaa-Asn三肽形成络合物的热力学参数，其中Xaa残基带有长度从1-5个碳原子变化的线性烷链。在丙氨酸衍生物中添加亚甲基后，结合亲和力增加，但进一步的扩链不会额外增强效力。乙基和正丙基衍生物的热力学特征与当时丁基和正戊基类似物的热力学特征基本相同。结晶学分析表明，除了具有正丙基、正丁基和正戊基的配体的结合构象中的侧链上存在Guche相互作用外，结构域和结合配体的结构高度相似。然而，通过在丙基类似物的侧链中引入AZ-双键来消除这种不利的相互作用并不会导致亲和力的增加。与配基结合的非极性表面埋藏量的增加与ΔH°的有利变化相关，但这些变化通常被−TΔS°的相应不利变化所抵消；ΔCp与埋藏的非极性表面的量变化几乎没有相关性。
Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1–5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl andn-propyl derivatives are virtually identical as are those for then-butyl andn-pentyl analogues. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands havingn-propyl,n-butyl, andn-pentyl groups. However, eliminating this unfavorable interaction by introducing aZ-double bond into the side chain of then-propyl analogue does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in ΔH°, but these are usually offset by corresponding unfavorable changes in −TΔS°; there is little correlation of ΔCpwith changes in the amount of buried nonpolar surface.