Some thermodynamic effects of varying nonpolar surfaces in protein-ligand interactions.
Some thermodynamic effects of varying nonpolar surfaces in protein-ligand interactions.
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在蛋白质 - 配体相互作用中不同非极性表面的一些热力学作用。
DOI：
10.1016/j.ejmech.2020.112771
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发表时间：
2020-12-15
影响因子：
6.7
通讯作者：
Martin SF
中科院分区：
文献类型：
--
作者：
Cramer DL;Cheng B;Tian J;Clements JH;Wypych RM;Martin SF
了解小分子的结构变化如何影响它们与靶蛋白的结合亲和力，对于改进合理药物设计策略至关重要。为了评估改变非极性基团的性质对结合熵和结合力的影响，我们设计并制备了一组Grb 2-SH 2结构域配体Ac-pTyr-Ac 6c-Asn-（CH 2）n-R，其中在pTyr+3位点的R基团的大小和静电性质是变化的。这些配体与Grb 2-SH 2结构域的复合物进行了评价，在一系列的研究中，其中的结合热力学进行了测定，使用等温滴定量热法，并结合相互作用进行了研究，在两个不同的复合物的晶体学研究。值得注意的是，添加非极性基团的pTyr+3网站导致更高的结合亲和力，但这些效果的大小和能量来源的R取代基的性质而异。例如，使用脂肪族R基团的结合亲和力的增强是由结合熵的更有利的变化驱动的，而芳基R基团通过结合熵和熵的更有利的变化的组合来提高结合自由能。然而，焓/熵补偿在这些关联中起着重要作用，并减轻了结合自由能的任何显著变化，其变化仅为0.8 kcal·mol−1，而R基团的静电性质和大小发生变化。晶体学研究表明，ΔG°或ΔH°的差异与埋藏的非极性表面积相关，但与极性或货车德瓦耳斯接触的总数无关。有序水分子的相对数量和pTyr+3侧链的相对有序性与−TΔS°的差异相关。总体而言，这些研究表明，埋葬的非极性表面可以导致增强的结合亲和力所产生的主导熵或疏水驱动的疏水效应，这取决于非极性R基团的静电性质。
Understanding how making structural changes in small molecules affects their binding affinities for targeted proteins is central to improving strategies for rational drug design. To assess the effects of varying the nature of nonpolar groups upon binding entropies and enthalpies, we designed and prepared a set of Grb2-SH2 domain ligands, Ac–pTyr–Ac6c–Asn–(CH2)n–R, in which the size and electrostatic nature of R groups at the pTyr+3 site were varied. The complexes of these ligands with the Grb2-SH2 domain were evaluated in a series of studies in which the binding thermodynamics were determined using isothermal titration calorimetry, and binding interactions were examined in crystallographic studies of two different complexes. Notably, adding nonpolar groups to the pTyr+3 site leads to higher binding affinities, but the magnitude and energetic origins of these effects vary with the nature of the R substituent. For example, enhancements to binding affinities using aliphatic R groups are driven by more favorable changes in binding entropies, whereas aryl R groups improve binding free energies through a combination of more favorable changes in binding enthalpies and entropies. However, enthalpy/entropy compensation plays a significant role in these associations and mitigates against any significant variation in binding free energies, which vary by only 0.8 kcal•mol−1, with changes in the electrostatic nature and size of the R group. Crystallographic studies show that differences in ΔG° or ΔH° correlate with buried nonpolar surface area, but they do not correlate with the total number of polar or van der Waals contacts. The relative number of ordered water molecules and relative order in the side chains at pTyr+3 correlate with differences in −TΔS°. Overall, these studies show that burial of nonpolar surface can lead to enhanced binding affinities arising from dominating entropy- or enthalpy-driven hydrophobic effects, depending upon the electrostatic nature of the apolar R group.
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影响因子：
16.6
作者：
Gerlach, Christof;Smolinski, Michael;Klebe, Gerhard
通讯作者：
Klebe, Gerhard
影响因子：
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García-Echeverría, C;Gay, B;Furet, P
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影响因子：
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