The role of protonation states in ligand-receptor recognition and binding.
The role of protonation states in ligand-receptor recognition and binding.
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DOI：
10.2174/1381612811319230004
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发表时间：
2013
影响因子：
3.1
通讯作者：
Alexov E
中科院分区：
文献类型：
--
作者：
Petukh M;Stefl S;Alexov E
在这篇综述中，我们讨论了质子化态在受体-配体相互作用中的作用，提供了实验证据和计算预测，即复杂的形成可能涉及具有异常 pKa 的可滴定基团，并且质子化态经常从未结合态变为结合态。这些质子化变化导致质子吸收/释放，进而导致结合的 pH 依赖性。事实上，实验数据强烈表明，几乎任何结合都是 pH 依赖性的，为了正确建模，必须在结合之前和之后正确分配质子化状态。当提供未结合蛋白质及其复合物的结构时，人们可以准确预测质子化状态；然而，如果必须在对接方案中预测结合状态或者结合或未结合的受体-配体的结构不可用，则建模变得更加复杂。在这些情况下出现的主要挑战是结合状态和质子化状态之间的耦合，以及可滴定基团的结合状态和电离状态引起的构象变化。此外，对质子化状态的任何评估，无论是在结合之前还是之后，都必须参考结合的 pH 值，而这通常是未知的。因此，即使可电离基团的 pKa 可以正确分配给未结合和结合状态，但在不知道实验 pH 的情况下，也无法分配相应的质子化状态，因此无法计算最终的质子吸收/释放。需要指出的是，虽然实验pH可能不是生理pH并且结合可能涉及质子摄取/释放，但天然受体-配体复合物有向特定的亚细胞或组织特征pH进化的趋势，在该pH下质子摄取/释放最小或不存在。
In this review we discuss the role of protonation states in receptor-ligand interactions, providing experimental evidences and computational predictions that complex formation may involve titratable groups with unusual pKa’s and that protonation states frequently change from unbound to bound states. These protonation changes result in proton uptake/release, which in turn causes the pH-dependence of the binding. Indeed, experimental data strongly suggests that almost any binding is pH-dependent and to be correctly modeled, the protonation states must be properly assigned prior to and after the binding. One may accurately predict the protonation states when provided with the structures of the unbound proteins and their complex; however, the modeling becomes much more complicated if the bound state has to be predicted in a docking protocol or if the structures of either bound or unbound receptor-ligand are not available. The major challenges that arise in these situations are the coupling between binding and protonation states, and the conformational changes induced by the binding and ionization states of titratable groups. In addition, any assessment of the protonation state, either before or after binding, must refer to the pH of binding, which is frequently unknown. Thus, even if the pKa’s of ionizable groups can be correctly assigned for both unbound and bound state, without knowing the experimental pH one cannot assign the corresponding protonation states, and consequently one cannot calculate the resulting proton uptake/release. It is pointed out, that while experimental pH may not be the physiological pH and binding may involve proton uptake/release, there is a tendency that the native receptor-ligand complexes have evolved toward specific either subcellular or tissue characteristic pH at which the proton uptake/release is either minimal or absent.
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影响因子：
7.3
作者：
Cozzini, P;Fornabaio, M;Mozzarelli, A
通讯作者：
Mozzarelli, A
影响因子：
3.3
作者：
Anand, Uttam;Kurup, Lisha;Mukherjee, Saptarshi
通讯作者：
Mukherjee, Saptarshi
DOI：
10.1046/j.1432-1033.2003.03917.x
发表时间：
2004-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Alexov, E
通讯作者：
Alexov, E
影响因子：
2.9
作者：
Davis JH;Dunican BF;Strobel SA
通讯作者：
Strobel SA
影响因子：
3.9
作者：
Demetriades, K;Coupland, JN;McClements, DJ
通讯作者：
McClements, DJ