Na Hyuntae, Song Guang
Department of Computer Science, Iowa State University, Ames, Iowa, 50011.
Proteins. 2015 Apr;83(4):757-70. doi: 10.1002/prot.24770. Epub 2015 Feb 28.
Ligand migration and binding are central to the biological functions of many proteins such as myoglobin (Mb) and it is widely thought that protein breathing motions open up ligand channels dynamically. However, how a protein exerts its control over the opening and closing of these channels through its intrinsic dynamics is not fully understood. Specifically, a quantitative delineation of the breathing motions that are needed to open ligand channels is lacking. In this work, we present and apply a novel normal mode-based method to quantitatively delineate what and how breathing motions open ligand migration channels in Mb and its mutants. The motivation behind this work springs from the observation that normal mode motions are closely linked to the breathing motions that are thought to open ligand migration channels. In addition, the method provides a direct and detailed depiction of the motions of each and every residue that lines a channel and can identify key residues that play a dominating role in regulating the channel. The all-atom model and the full force-field employed in the method provide a realistic energetics on the work cost required to open a channel, and as a result, the method can be used to efficiently study the effects of mutations on ligand migration channels and on ligand entry rates. Our results on Mb and its mutants are in excellent agreement with MD simulation results and experimentally determined ligand entry rates.
配体迁移和结合是许多蛋白质（如肌红蛋白，Mb）生物学功能的核心，人们普遍认为蛋白质的呼吸运动能动态地打开配体通道。然而，蛋白质如何通过其内在动力学对这些通道的开闭进行控制，目前尚未完全清楚。具体而言，目前缺乏对打开配体通道所需呼吸运动的定量描述。在这项工作中，我们提出并应用了一种基于简正模式的新方法，以定量描述Mb及其突变体中打开配体迁移通道的呼吸运动是什么以及如何进行。这项工作背后的动机源于这样的观察：简正模式运动与被认为能打开配体迁移通道的呼吸运动密切相关。此外，该方法能直接且详细地描绘构成通道的每个残基的运动，并能识别在调节通道中起主导作用的关键残基。该方法中使用的全原子模型和完整力场提供了打开通道所需功的实际能量学信息，因此，该方法可用于有效研究突变对配体迁移通道和配体进入速率的影响。我们对Mb及其突变体的研究结果与分子动力学模拟结果以及实验测定的配体进入速率高度吻合。
