Competitive Coordination and Structural Evolution of Phenylalanine–Mg 2+ Complexes in Microaqueous Environments: Insights from DFT and Molecular Dynamics Simulations

This study elucidates the coordination evolution and competitive–cooperative interaction between phenylalanine and Mg 2+ in microaqueous environments using DFT calculations, AIMD, and WT-metadynamics simulations. Results reveal a hydration-driven shift in the coordination mode from tridentate chelation (carboxyl O, amino N, phenyl π-system) to monodentate carboxyl binding, accompanied by a geometric evolution from a four-coordinate sawhorse to a stable six-coordinate octahedron via a trigonal bipyramidal intermediate. Topology, NBO, and EDA-NOCV analyses demonstrate water’s dual role as a competitive ligand and structural regulator, inducing a zwitterionic transition that anomalously enhances the Mg 2+ –carboxyl interaction at moderate hydration ( n = 3–4). Notably, AdNDP analysis confirms the preservation of phenyl ring aromaticity. WT-metadynamics simulations validate the thermodynamic stability of the octahedral structure in aqueous solution, providing critical insight into Mg 2+ –amino acid recognition.