How trehalose has exceptional property in helping biomolecules preserve their native structures remains a subject of active research. Running molecular dynamics simulations on a model protein in low-concentrated trehalose solution and pure water, respectively, the present study verifies the ability of trehalose in stabilizing protein native structure and provides a comprehensive atomic-level picture of the molecular interactions among protein, trehalose, and water in their mixed solution. Trehalose directly interacts to and meanwhile affects the interactions between the other species via hydrogen bonding: 1) trehalose molecules are clustered through inter-molecular hydrogen bonding interaction; 2) trehalose forms hydrogen bond with water which influences the strength of water-water hydrogen bonding network but does not impair protein-water hydrogen bonding; 3) trehalose is accessible to form hydrogen bonds towards protein and simultaneously replace water molecules around protein which reduces the hydrogen bonding possibility from water to protein, in accordance with water replacement scenario.

Trehalose Stabilizing Protein in a Water Replacement Scenario: Insights from Molecular Dynamics Simulation