Unraveling the Complex Hydrogen-Bonding and Solvation Patterns of Fructose Tautomers via Complementary AIMD and Classical MD Simulations.

Understanding the molecular-level hydration of fructose tautomers remains a challenge due to their rapid interconversion and structural complexity. A dual-scale approach was employed, combining long-time classical molecular dynamics (MD) and ab initio molecular dynamics (AIMD) to elucidate differences in the hydrogen-bonding networks of both pyranose and furanose tautomers with statistical and electronic accuracy. Our simulations highlight the inherent competition between intra- and intermolecular hydrogen bonds, driven by the limited number of hydroxyl donor and acceptor sites. Crucially, the formation of these internal bonds is driven by ring puckering in the flexible furanoses alongside the spatial orientation of the hydroxymethyl groups in both tautomer families. This structural interplay indirectly influences the entire intermolecular solvation shell, comprising both hydrophilic and hydrophobic regions. By correlating these competing intra- and intermolecular patterns with Bader charges and water dipole moments, we establish a quantitative electronic-structure basis for carbohydrate solvation. These insights provide a comprehensive atomistic framework that deepens our understanding of biologically relevant processes, such as recognition and docking efficiency within metabolic enzymes.