A Preliminary DFT Screening of Zn(II) Coordination Models for Guanidine, Galegine, Metformin, and L-Arginine: Protonation, First-Shell Hydration, and Electronic Descriptors

Zinc dyshomeostasis has been associated with neurodegenerative processes, but molecular-level models of Zn(II) recognition by guanidino- and biguanide-containing molecules must account for protonation, conformational flexibility, and competition with the first hydration shell. Here, a hierarchical density functional theory strategy was applied to guanidine, galegine, metformin, and L-arginine. Neutral ligands, relevant protonated forms, and simplified [Zn(L)]2+ adducts were examined using the Becke three-parameter Lee–Yang–Parr (B3LYP) functional with the 6-311+G(d,p) basis set and integral equation formalism polarizable continuum model (IEFPCM) water solvation (Set I), whereas [Zn(H2O)6]2+ and explicitly hydrated [Zn(L)(H2O)5]2+ first-shell substitution models were evaluated using B3LYP with Grimme D3 dispersion and Becke–Johnson damping [D3(BJ)]/def2-SVP/IEFPCM(water) (Set II). Harmonic-frequency analyses supported the reported stationary structures as local minima within the corresponding computational models. Within Set I, the simplified [Zn(L)]2+ adducts display Zn-N distances of 1.924–1.935 Å. Within the separate Set II hydrated coordination models, direct Zn-N coordination is retained with Zn-N distances of 2.007–2.028 Å. Protonation shifts the molecular electrostatic potential toward positive values around guanidino/biguanide fragments, reducing electrostatic donor accessibility. Targeted torsional checks further show that flexible-ligand descriptors are conformer-dependent; for neutral L-arginine, the A6 carboxylic-OH rotamer adopted for the final analysis has a frontier-orbital separation of 6.214 eV, compared with 5.984 eV for the initial pre-A6 conformer. These results define a preliminary descriptor-based electronic-structure and first-shell coordination framework rather than a prediction of binding affinity, predominant physiological speciation, or pharmacological activity.