Protein-ligand interactions: thermodynamic effects associated with increasing nonpolar surface area.
Protein-ligand interactions: thermodynamic effects associated with increasing nonpolar surface area.
复制标题
蛋白质-配体相互作用：与增加非极性表面积相关的热力学效应。
DOI：
10.1021/ja2068752
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发表时间：
2011
影响因子：
15
通讯作者：
Martin,StephenF
中科院分区：
文献类型：
--
作者：
Myslinski,JamesM;DeLorbe,JohnE;Clements,JohnH;Martin,StephenF
确定了Grb 2 SH 2结构域与Ac-pTyr-Xaa-Asn衍生的三肽之间形成复合物的热力学参数，其中Xaa残基是环大小从三元到七元变化的α，α-脂环族氨基酸。虽然六元环和七元环类似物是近似等效的，但具有三至六元环的那些的结合亲和力随着环大小而递增，因为越来越有利的结合熵支配越来越不利的结合熵，这一发现与疏水驱动的疏水效应一致。晶体学分析表明，复合物结构的唯一显著差异在于结构域与Xaa残基中的亚甲基之间的货车范德华接触的数量。埋置非极性表面积与结合自由能和焓成正相关，而与ΔCp不相关。从蛋白质-配体界面置换水分子不一定反映在结合熵的有利变化中。这些研究结果突出了一些fallibilities与普遍持有的观点的关系，蛋白质-配体相互作用的结构和能量，并有显着的影响配体设计。
Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and Ac-pTyr-Xaa-Asn derived tripeptides in which the Xaa residue is an α,α-cycloaliphatic amino acid that varies in ring size from three- to seven-membered. Although the six- and seven-membered ring analogs are approximately equipotent, binding affinities of those having three- to six-membered rings increase incrementally with ring size becauseincreasingly more favorable binding enthalpies dominate increasingly less favorable binding entropies, a finding consistent with an enthalpy-driven hydrophobic effect. Crystallographic analysis reveals that the only significant differences in structures of the complexes are in the number of van der Waals contacts between the domain and the methylene groups in the Xaa residues. There is a positive correlation between buried nonpolar surface area and binding free energyandenthalpy, but not with ΔCp. Displacing a water molecule from a protein–ligand interface is not necessarily reflected in a favorable change in binding entropy. These findings highlight some of the fallibilities associated with commonly held views of relationships of structure and energetics in protein–ligand interactions and have significant implications for ligand design.