Privat Cristian, Madurga Sergio, Mas Francesc, Rubio-Martinez Jaime
Department of Material Science and Physical Chemistry & Research Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, C/Martí i Franquès 1, 08028 Barcelona, Spain.
Polymers (Basel). 2021 Sep 28;13(19):3311. doi: 10.3390/polym13193311.
An accurate description of the protonation state of amino acids is essential to correctly simulate the conformational space and the mechanisms of action of proteins or other biochemical systems. The pH and the electrochemical environments are decisive factors to define the effective pKa of amino acids and, therefore, the protonation state. However, they are poorly considered in Molecular Dynamics (MD) simulations. To deal with this problem, constant pH Molecular Dynamics (cpHMD) methods have been developed in recent decades, demonstrating a great ability to consider the effective pKa of amino acids within complex structures. Nonetheless, there are very few studies that assess the effect of these approaches in the conformational sampling. In a previous work of our research group, we detected strengths and weaknesses of the discrete cpHMD method implemented in AMBER when simulating capped tripeptides in implicit solvent. Now, we progressed this assessment by including explicit solvation in these peptides. To analyze more in depth the scope of the reported limitations, we also carried out simulations of oligopeptides with distinct positions of the titratable amino acids. Our study showed that the explicit solvation model does not improve the previously noted weaknesses and, furthermore, the separation of the titratable amino acids in oligopeptides can minimize them, thus providing guidelines to improve the conformational sampling in the cpHMD simulations.
准确描述氨基酸的质子化状态对于正确模拟蛋白质或其他生化系统的构象空间及作用机制至关重要。pH值和电化学环境是决定氨基酸有效pKa值进而决定其质子化状态的关键因素。然而，在分子动力学（MD）模拟中，这些因素很少被考虑。为解决这一问题，近几十年来已开发出恒定pH分子动力学（cpHMD）方法，该方法在考虑复杂结构中氨基酸的有效pKa值方面展现出强大能力。尽管如此，评估这些方法对构象采样影响的研究却非常少。在我们研究小组之前的一项工作中，我们检测了在隐式溶剂中模拟封端三肽时，AMBER中实现的离散cpHMD方法的优缺点。现在，我们通过在这些肽中加入显式溶剂化来推进这项评估。为更深入地分析所报道局限性的范围，我们还对可滴定氨基酸处于不同位置的寡肽进行了模拟。我们的研究表明，显式溶剂化模型并未改善之前指出的缺点，此外，寡肽中可滴定氨基酸的分离可将这些缺点最小化，从而为改进cpHMD模拟中的构象采样提供指导。
