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

本文采用计算和理论相结合的方法研究了液滴、气态和块状环境中决定大分子电荷的因素以及电荷与大分子构象的关系。电荷诱导的大分子构象变化是DNA、蛋白质等生物大分子的一个重要过程。该研究的其他实际应用还包括电喷雾质谱（ESMS），这是一种主要用于分析生物分子（如蛋白质、DNA、多糖）的分析技术。为了理解在电喷雾电离过程中发生的过程，需要了解大分子在散装、液滴环境和气态状态下的电荷和构象。在这些实验中，电喷雾电离通过带电液滴将大分子从散装溶液转移到气态。影响液滴中大分子电荷态分布的因素包括：液滴环境中被分析物与溶剂的相互作用、液滴酸度的变化、液滴中溶剂的蒸发速率与巨量离子的去质子化速率、巨量离子从液滴中释放的机理以及电喷雾仪器的操作细节。我们使用超越直接分子动力学和蒙特卡罗方法的先进分子模拟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。这些罕见的波动是通过模拟和统计力学中激活过程的方法捕获的。本研究旨在了解大分子充电的基本过程，为ESMS方法中产生信号的过程奠定理论基础。我们为构象变化的抽样而开发的计算方法可以用于比我们研究的更广泛的问题。此外，我们在气滴和体环境中的研究将增强我们对决定生物大分子构象的相互作用的认识。

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.