Sucrose versus\nTrehalose: Observations from Comparative\nStudy Using Molecular Dynamics Simulations

Binary mixtures of sucrose and trehalose in water were\ninvestigated\nusing classical molecular dynamics (MD) simulations and free energy\ncalculations. By classical MD simulations, the behavior of sugars\nwas studied across the entire range of concentrations, from 0 to 100\nwt % of water. Sugar–sugar and sugar–water affinities\nin diluted systems were in focus when using umbrella sampling and\nwell-tempered metadynamics calculations. Moreover, in classical MD\nsimulations, two approaches for system equilibration were applied:\nin the first, mixtures were preheated (using simulated annealing)\nbefore simulations under desired conditions, while in the second,\nno preliminary heating was used. It was discovered that sucrose has\na stronger tendency to aggregate than trehalose, while the latter\nforms more hydrogen bonds with water. Below the concentration of 10\nwt % of water, the number of hydrogen bonds between sugars is higher\nthan the number of hydrogen bonds between sugars and water. The free\nenergy calculations and hydrogen bonding analysis reveal certain dissimilarities\nin the hydration of oxygen-containing molecular groups. While there\nare noticeable differences in the hydration of various hydroxyl groups\nin sucrose and trehalose, all hydroxyl groups are clearly more hydrated\nthan the ether oxygens in both sugars. Three factors contribute to\nthe lower hydration of ether oxygens: they do not donate hydrogen\nbonds, they are slightly less polar than the oxygen atoms in hydroxyl\ngroups, and they are less accessible to the solvent. Moreover, hydroxyl\ngroups play the main role in binding water, and the geometry of trehalose\nis energetically preferable compared to the geometry of sucrose. Effects\nof preheating were demonstrated at water concentrations below 70 wt\n%, with more significant differences between mixtures observed at\nwater concentrations below 40 wt %. Disaccharides bind stronger to\neach other and weaker with water molecules in preheated systems than\nin mixtures that were not preheated. The hydroxyl groups of sucrose\nand trehalose in preheated mixtures rotate slower than in systems\nthat did not undergo thermal treatment. Therefore, while preheating\nis not necessary for liquid solutions, it is vital for the equilibration\nof samples in their amorphous solid state. In the experimental community,\nthese findings are relevant for decision-making when choosing one\nof the disaccharides as a preservative.