Unraveling the Weak Yet Vital: A High‐Level DFT Exploration of Non‐Covalent Interactions in Hydrated Polyethylene Glycol and Methoxy Polyethylene Glycol Systems

Abstract

A detailed theoretical investigation is presented to elucidate the non‐covalent interactions governing the structural stability of polyethylene glycol (PEG) and methoxy polyethylene glycol (MPEG) complexes with explicit water molecules. Calculations were performed using density functional theory (DFT) at the M06‐2X/cc‐pVDZ level. Optimized geometries reveal that polymer–water interactions are thermodynamically favorable, supporting the spontaneous formation of stable complexes. Molecular electrostatic potential (MEP) maps were generated to identify chemically reactive regions and preferred interaction sites. To explore the electronic origin of these interactions, natural bond orbital (NBO) analysis was employed, which confirmed charge transfer between water molecules and PEG/MPEG units. Non‐covalent interaction (NCI) analysis, complemented by the independent gradient model based on Hirshfeld partition (IGMH), highlighted weak hydrogen bonding primarily between ether oxygen atoms of PEG/MPEG and hydrogen atoms of water. Atoms in molecules (AIM) topological analysis further confirmed these findings by locating bond critical points consistent with hydrogen bonding. Due to the limitation of IGMH in treating only two fragments, analyses were conducted using single water molecules at each site to map local interactions. This comprehensive study provides molecular‐level insights into the weak but crucial hydrogen bonding interactions that enhance solubility, biocompatibility, and functionality of PEG–H2O and MPEG–H2O systems in pharmaceutical and material applications.