An unconventional ligand-binding mechanism of substrate-binding proteins: MD simulation and Markov state model analysis of BtuF
An unconventional ligand-binding mechanism of substrate-binding proteins: MD simulation and Markov state model analysis of BtuF
复制标题
底物结合蛋白的非常规配体结合机制：BtuF的MD模拟和马尔可夫状态模型分析
DOI：
10.1002/jcc.25798
复制
发表时间：
2019
影响因子：
3
通讯作者：
Wang Wenning
中科院分区：
文献类型：
--
作者：
Wang Dongdong;Weng Jingwei;Wang Wenning
在传统的“捕蝇草”机制中，底物结合蛋白（SBP）在开放和闭合构象之间相互转换。在配体结合时，SBPs与结合在两个结构域的界面处的配体形成紧密闭合的构象。这种机制后来受到许多III型SBP的挑战，例如维生素B12结合蛋白BtuF，其中脱辅基和全态蛋白采用非常相似的构象。在这里，我们结合分子动力学模拟和马尔可夫状态模型分析来研究apo-和B12-结合的BtuF的构象动力学。结果表明，晶体结构代表了BtuF的唯一稳定构象。同时，apo‐和holo‐BtuF都经历了大规模的域间运动，能量消耗很小。B12结合对域间运动几乎没有限制，这表明配体结合亲和力被holo-BtuF的剩余构象熵增强。这些结果揭示了SBPs配体识别机制的新范式。© 2019 Wiley Periodicals，Inc.
In conventional “Venus Flytrap” mechanism, substrate‐binding proteins (SBPs) interconvert between the open and closed conformations. Upon ligand binding, SBPs form a tightly closed conformation with the ligand bound at the interface of two domains. This mechanism was later challenged by many type III SBPs, such as the vitamin B12‐binding protein BtuF, in which the apo‐ and holo‐state proteins adopt very similar conformations. Here, we combined molecular dynamics simulation and Markov state model analysis to study the conformational dynamics of apo‐ and B12‐bound BtuF. The results indicate that the crystal structures represent the only stable conformation of BtuF. Meanwhile, both apo‐ and holo‐BtuF undergo large‐scale interdomain motions with little energy cost. B12binding casts little restraints on the interdomain motions, suggesting that ligand binding affinity is enhanced by the remaining conformational entropy of holo‐BtuF. These results reveal a new paradigm of ligand recognition mechanism of SBPs. © 2019 Wiley Periodicals, Inc.