Mathematical and Computational Strategies for Predicting Joint Solubility of Rebaudioside A and Rebaudioside D

Rebaudiosides A and D are sweeteners derived from the Stevia plant and are 300 times sweeter than sugar. They are more soluble together than individually, an example of enhanced joint solubility. This project assesses how to speed up molecular dynamics based joint solubility calculations. Key to calculating solubility is evaluating the chemical potential from the simulated configurations. We provide a map of options for speeding up these calculations, including their relative speeds and accuracy. We find that the most efficient and accurate methods are Free Energy Perturbation, which calculates free energy differences between related states, and Umbrella Sampling, which biases simulations to enhance sampling of otherwise inaccessible regions of configurational space. Future work will focus on improving the accuracy of the method comparisons, identifying failure modes, and extending the assessment to hybrid approaches and alternative force fields, with the aim of integrating these methods into commercial software.