Protein-ligand binding enthalpies from near-millisecond simulations: Analysis of a preorganization paradox
Protein-ligand binding enthalpies from near-millisecond simulations: Analysis of a preorganization paradox
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DOI：
10.1063/1.5027439
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发表时间：
2018-08-21
影响因子：
4.4
通讯作者：
Gilson, Michael K.
中科院分区：
文献类型：
--
作者：
Li, Amanda;Gilson, Michael K.
蛋白质-配体结合的量热研究有时会产生难以理解的热力学数据。今天，分子模拟可以用来寻求洞察这样的热量难题，当模拟和实验分歧，结果可以有效地激励进一步改进计算方法。在这里，我们应用近毫秒的持续时间模拟估计的相对结合的Grb 2 SH 2结构域的四个肽配体的bindingpies。配体分为匹配的对，其中每对的一个成员具有额外的键，该键预先组织配体用于结合，因此由于构型熵的较小损失，可以预期有利于熵结合。量热研究表明，约束配体实际上比柔性配体更紧密地结合SH 2结构域，但矛盾的是，约束配体的亲和力的改善是亲合力的，而不是熵。本焓计算产生相反的趋势，因为它们表明，柔性配体结合更强。此外，发现小的相对结合势是结构组分如配体和结合位点残基的能量的大差异的平衡。因此，相对结合常数与实验的偏差代表了这些大数值之间的微小差异，因此可能特别容易受到误差的影响，例如由于力场中的近似值。我们还计算了一阶估计结合的构型熵的变化。这些也可以说是自相矛盾的，因为它们倾向于支持柔性配体的结合。这一悖论的部分原因是，更刚性的约束配体减少结合位点残基的熵比它们的灵活的类似物，至少在模拟。这一结果提供了一个相当普遍的反驳预期，预制配体应该与更有利的结合熵，其他事情是平等的。由AIP出版社出版。
Calorimetric studies of protein-ligand binding sometimes yield thermodynamic data that are difficult to understand. Today, molecular simulations can be used to seek insight into such calorimetric puzzles, and, when simulations and experiments diverge, the results can usefully motivate further improvements in computational methods. Here, we apply near-millisecond duration simulations to estimate the relative binding enthalpies of four peptidic ligands with the Grb2 SH2 domain. The ligands fall into matched pairs, where one member of each pair has an added bond that preorganizes the ligand for binding and thus may be expected to favor binding entropically, due to a smaller loss in configurational entropy. Calorimetric studies have shown that the constrained ligands do in fact bind the SH2 domain more tightly than the flexible ones, but, paradoxically, the improvement in affinity for the constrained ligands is enthalpic, rather than entropic. The present enthalpy calculations yield the opposite trend, as they suggest that the flexible ligands bind more exothermically. Additionally, the small relative binding enthalpies are found to be balances of large differences in the energies of structural components such as ligand and the binding site residues. As a consequence, the deviations from experiment in the relative binding enthalpies represent small differences between these large numbers and hence may be particularly susceptible to error, due, for example, to approximations in the force field. We also computed first-order estimates of changes in configurational entropy on binding. These too are, arguably, paradoxical, as they tend to favor binding of the flexible ligands. The paradox is explained in part by the fact that the more rigid constrained ligands reduce the entropy of binding site residues more than their flexible analogs do, at least in the simulations. This result offers a rather general counterargument to the expectation that preorganized ligands should be associated with more favorable binding entropies, other things being equal. Published by AIP Publishing.