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

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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.