Ramasanoff Ruslan R, Sokolov Petr A
Sevastopol State University, Universitetskaya 33, 299053, Sevastopol, Russia.
Sevastopol State University, Universitetskaya 33, 299053, Sevastopol, Russia; Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034, Saint Petersburg, Russia.
J Mol Graph Model. 2023 Jan;118:108338. doi: 10.1016/j.jmgm.2022.108338. Epub 2022 Sep 22.
We report a novel model of the selective binding mechanism of adenosine-specific DNA aptamer. Our theoretical investigations of AMP (Adenosine monophosphate) dissociation from aptamer-AMP complexes reveals new details of aptamer molecular specificity and stabilisation factors. Umbrella sampling MD calculations using parmbsc1 force field shows that the disordered structure of the internal loop of the unbound aptamer hairpin has a characteristic packing of guanines, which prevents barrier-free penetration of ligands into the site cavity. Also, this disordered structure of the unbound aptamer has a network of hydrogen bonds stabilising the cavity near the target guanines within the binding sites during the whole binding process. We suggested that the first AMP molecule binds to the disordered structure of the site closest to the aptamer hairpin stem and spends some free energy on ordering of the internal loop. Then the second AMP molecule binds to the ordered site closest to the aptamer hairpin loop with a lower energy gain. As a result, the induced-fit binding model is the most applicable for this aptamer and does not contradict the modern experimental NMR and calorimetry data.
我们报道了一种腺苷特异性DNA适配体选择性结合机制的新模型。我们对AMP（单磷酸腺苷）从适配体-AMP复合物中解离的理论研究揭示了适配体分子特异性和稳定因素的新细节。使用parmbsc1力场的伞形采样分子动力学计算表明，未结合的适配体发夹内部环的无序结构具有鸟嘌呤的特征堆积，这阻止了配体无障碍地进入位点腔。此外，未结合的适配体的这种无序结构具有氢键网络，在整个结合过程中稳定结合位点内目标鸟嘌呤附近的腔。我们认为，第一个AMP分子与最靠近适配体发夹茎的位点的无序结构结合，并在内部环的有序化上花费一些自由能。然后，第二个AMP分子以较低的能量增益与最靠近适配体发夹环的有序位点结合。因此，诱导契合结合模型最适用于这种适配体，并且与现代实验核磁共振和量热数据不矛盾。
