Applications of efficient simulation methods in the study of charging and conformations of macromolecules

我们使用计算和理论的方法来研究的因素，确定在液滴，气体和散装环境中的大分子的充电和充电的大分子的构象的关系。电荷诱导大分子构象变化是生物大分子如DNA、蛋白质等的重要过程。该研究的其他实际应用是电喷雾质谱法（ESMS），这是一种分析技术，主要用于分析生物分子，如蛋白质，DNA，聚乙烯。为了理解电喷雾电离中发生的过程，需要了解大分子在本体、液滴环境和气态下的充电和构象。在这些实验中，电喷雾电离通过带电液滴将大分子从本体溶液转移到气态。影响液滴中大分子电荷态分布的因素包括液滴环境中分析物与溶剂之间的相互作用、液滴中酸度的变化、液滴中溶剂的蒸发速率与大分子离子的去质子化速率、大分子离子从液滴中的释放机制以及电喷雾仪器的操作细节。我们使用先进的分子模拟方法，超越了直接的分子动力学和蒙特卡罗方法来研究这些因素。几乎所有的因素都是由溶剂和大分子中罕见的分子波动决定的。这些罕见的波动被模拟和统计力学中的激活过程方法捕获。该研究旨在了解大分子充电的基本过程，并为ESMS方法中产生信号的过程奠定理论基础。我们开发的构象变化的采样的计算方法，可以用于更广泛的一类问题比我们研究。此外，我们在气滴和散装环境中的研究将提高我们的知识，确定生物大分子的构象的相互作用。

We use computational and theoretical methods to study the factors that determine the charging of macromolecules in droplet, gaseous and bulk environments and the relation of charging to the conformations of the macromolecules. Charge-induced conformational change of macromolecules is an important process in biological macromolecules such as DNA and proteins. Other practical applications of the study are found in electrospray mass spectrometry (ESMS), which is an analytical technique used for the analysis mainly of biological molecules such as proteins, DNA, poly-saccharides. To understand the processes that take place in electrospray ionization, knowledge of the charging and the conformations of a macromolecule is required in bulk, droplet environment and gaseous state. In these experiments, electrospray ionization transfers macromolecules from the bulk solution into the gaseous state via charged droplets. The factors that affect the charge state distribution of the macromolecules in the droplet include the interactions between the analyte and the solvent in the droplet environment, acidity changes in the droplet, evaporation rate of the solvent vs. deprotonation rate of the macroions in the droplet, release mechanisms of macroions from droplets, and details in the operation of the electrospray instrument. We use advanced molecular simulation methods that are beyond direct molecular dynamics and Monte Carlo methods to study these factors. Almost all the factors are determined by rare molecular fluctuations in the solvent and macromolecules. These rare fluctuations are captured by methods for activated processes in simulations and statistical mechanics. The study aims at understanding fundamental processes in the charging of macromolecules and laying the theoretical foundation for processes that give rise to the signals in the ESMS methods. The computational methodology that we develop for the sampling of the conformational changes can be used in a broader class of problems than those we study. Moreover, our studies in the gas-droplet and bulk environment will enhance our knowledge on the interactions that determine the conformations of biological macromolecules.