Huang WenJuan, Blinov Nikolay, Wishart David S, Kovalenko Andriy
Department of Mechanical Engineering, University of Alberta , Edmonton, AB T6G 2G8, Canada.
J Chem Inf Model. 2015 Feb 23;55(2):317-28. doi: 10.1021/ci500520q. Epub 2015 Jan 26.
Maltose-binding protein is a periplasmic binding protein responsible for transport of maltooligosaccarides through the periplasmic space of Gram-negative bacteria, as a part of the ABC transport system. The molecular mechanisms of the initial ligand binding and induced large scale motion of the protein's domains still remain elusive. In this study, we use a new docking protocol that combines a recently proposed explicit water placement algorithm based on the 3D-RISM-KH molecular theory of solvation and conventional docking software (AutoDock Vina) to explain the mechanisms of maltotriose binding to the apo-open state of a maltose-binding protein. We confirm the predictions of previous NMR spectroscopic experiments on binding modes of the ligand. We provide the molecular details on the binding mode that was not previously observed in the X-ray experiments. We show that this mode, which is defined by the fine balance between the protein-ligand direct interactions and solvation effects, can trigger the protein's domain motion resulting in the holo-closed structure of the maltose-binding protein with the maltotriose ligand in excellent agreement with the experimental data. We also discuss the role of water in blocking unfavorable binding sites and water-mediated interactions contributing to the stability of observable binding modes of maltotriose.
麦芽糖结合蛋白是一种周质结合蛋白，作为ABC转运系统的一部分，负责将麦芽寡糖运输穿过革兰氏阴性菌的周质空间。蛋白质结构域最初的配体结合以及由此引发的大规模运动的分子机制仍然不清楚。在本研究中，我们使用了一种新的对接方案，该方案结合了最近基于3D-RISM-KH溶剂化分子理论提出的显式水放置算法和传统对接软件（AutoDock Vina），以解释麦芽三糖与麦芽糖结合蛋白的脱辅基开放状态的结合机制。我们证实了先前关于配体结合模式的核磁共振光谱实验的预测。我们提供了X射线实验中未观察到的结合模式的分子细节。我们表明，这种由蛋白质-配体直接相互作用和溶剂化效应之间的精细平衡所定义的模式，可以触发蛋白质结构域的运动，从而形成含有麦芽三糖配体的麦芽糖结合蛋白的全酶封闭结构，这与实验数据非常吻合。我们还讨论了水在阻断不利结合位点以及水介导的相互作用对麦芽三糖可观察到的结合模式稳定性的贡献方面的作用。
