Steered molecular dynamics simulations of ligand-receptor interaction in lipocalins
Steered molecular dynamics simulations of ligand-receptor interaction in lipocalins
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DOI：
10.1007/s00249-010-0638-3
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发表时间：
2011-02-01
影响因子：
2
通讯作者：
Akola, Jaakko
中科院分区：
文献类型：
--
作者：
Kalikka, Janne;Akola, Jaakko
视黄醇结合蛋白（RBP）和一个工程脂质运载蛋白，DigA 16，已经使用分子动力学模拟进行了研究。特别强调已被放置在解释的RBP-视黄醇和DigA 16-洋地黄毒苷复合物中的配体-受体相互作用，并已进行了10-20 ns的引导分子动力学模拟的配体驱逐过程。地高辛结合在DigA 16的空腔深处，除了与芳香侧链的疏水性货车德瓦尔斯相互作用外，还形成几个稳定的氢键。在模拟过程中，配体结合腔内的四个结晶水分子仍然被困在其中。RBP的强疏水性受体位点与DigA 16有很大不同，配体吸引的主要来源来自苯基侧链。地高辛和DigA 16之间的氢键导致DigA 16和RBP中配体去除的断裂力不同。突变的DigA 16残基贡献了地高辛与DigA 16的相互作用能的大约一半，其中，能量上最重要的是残基His 35、Arg 58、Ser 87、Tyr 88和Phe 114。潜在的“传感器回路”被发现为两个受体。这些分别是DigA 16和RBP的残基114-121和63-67之间的离群环，并且它们位于配体结合腔的入口附近。特别是，残基Glu 119（DigA 16）和Leu 64（RBP）对于传感是关键的。已估计的配体结合能的结合亲和力的线性响应近似的基础上，通过使用先前的参数化维甲酸和RBP。
Retinol binding protein (RBP) and an engineered lipocalin, DigA16, have been studied using molecular dynamics simulations. Special emphasis has been placed on explaining the ligand-receptor interaction in RBP-retinol and DigA16-digoxigenin complexes, and steered molecular dynamics simulations of 10-20 ns have been carried out for the ligand expulsion process. Digoxigenin is bound deep inside the cavity of DigA16 and forms several stable hydrogen bonds in addition to the hydrophobic van der Waals interaction with the aromatic side-chains. Four crystalline water molecules inside the ligand-binding cavity remain trapped during the simulations. The strongly hydrophobic receptor site of RBP differs considerably from DigA16, and the main source of ligand attraction comes from the phenyl side-chains. The hydrogen bonds between digoxigenin and DigA16 cause the rupture forces on ligand removal in DigA16 and RBP to differ. The mutated DigA16 residues contribute approximately one-half of the digoxigenin interaction energy with DigA16 and, of these, the energetically most important are residues His35, Arg58, Ser87, Tyr88, and Phe114. Potential "sensor loops" were found for both receptors. These are the outlier loops between residues 114-121 and 63-67 for DigA16 and RBP, respectively, and they are located near the entrance of the ligand-binding cavity. Especially, the residues Glu119 (DigA16) and Leu64 (RBP) are critical for sensing. The ligand binding energies have been estimated based on the linear response approximation of binding affinity by using a previous parametrization for retinoids and RBP.