Ab initio study of molecular properties of l -tyrosine

**Background:** l-Tyrosine is a non-essential amino acid that serves as a precursor for monoaminergic neurotransmitters (dopamine, adrenaline, noradrenaline) and thyroid hormones. In neutral pH, it exists as a zwitterion, but in vacuo it adopts the canonical aminoacid form. Understanding its molecular properties, especially redox behavior, is important because tyrosine is non-innocent in redox processes and may form cytotoxic amyloid-like assemblies implicated in neurodegeneration. Additionally, tyrosine crystallization during nitisinone-induced hypertyrosinemia can cause corneal keratopathy. This study aims to compute a set of molecular descriptors for both forms in vacuo and in water using high-level ab initio calculations.

**Methods:** The authors employed Hartree–Fock (HF) MO-LCAO-SCF calculations with the def2-TZVP basis set (469 basis functions) and improved correlation energy via MP2 perturbation theory. Solvent effects were modeled using the Conductor-like Polarizable Continuum Model (CPCM) with water parameters (ε_r = 80.4). Geometry optimization was performed for neutral, cationic, and anionic species. Vertical ionization energy (E_i) and electron affinity (E_eg) were calculated from energy differences of charged vs. neutral species. Adiabatic values were obtained from fully optimized geometries of each ion. Thermodynamic functions (inner energy U, enthalpy H, entropy S, Gibbs energy G) were derived from complete vibrational analysis. Absolute redox potentials were computed from reaction Gibbs energies: E_abs^ø(L^0/L^q) [V] = –Δ_rG^ø[J mol⁻¹]/zF, with F = 96,485 C·mol⁻¹ and z = 1. Additionally, density functional theory (DFT) with the B3LYP hybrid functional was used for full geometry optimization of neutral and ionized forms. Molecular descriptors included HOMO/LUMO energies, dipole moment, quadrupole moment, dipole polarizability, Mulliken electronegativity (χ_M), Pearson hardness (η_P), and electrophilicity index (ω). Cluster analysis (Ward's method, Euclidean norm) was applied to compare l-tyrosine with nine related neurotransmitters and trace amines.

**Key Results:** For the aminoacid form in vacuo, the vertical ionization energy (E_i) was 166 kcal mol⁻¹ (ΔSCF) and 206 kcal mol⁻¹ (MP2); electron affinity (E_eg) was 51 and 41 kcal mol⁻¹, respectively. In water, these values decreased: E_i = 117 (ΔSCF) and 160 (MP2) kcal mol⁻¹; E_eg = 2 (ΔSCF) and –8 (MP2) kcal mol⁻¹. The zwitterionic form in water showed similar values: E_i = 118.3 (ΔSCF) and 162.7 (MP2) kcal mol⁻¹; E_eg = 1.3 (ΔSCF) and –8.3 (MP2) kcal mol⁻¹. The dipole moment of the zwitterion (16.31 D) was more than 10 times higher than the aminoacid form (2.189 D). The zwitterion was more stable than the aminoacid form by ΔE = –3.5 kcal mol⁻¹ (B3LYP) and ΔG^ø = –1.96 kcal mol⁻¹. Adiabatic calculations (B3LYP) gave absolute reduction potentials: for aminoacid form A1, E_red^ø = 1.31 V; for A2, 1.20 V; for zwitterion, 1.27 V. The oxidation potentials were –5.71, –5.81, and –5.86 V, respectively. Cluster analysis showed that l-tyrosine (aminoacid) is most similar to phenylalanine, octopamine, and noradrenaline (cluster I).

**Clinical Implications:** This study provides a detailed electronic structure and redox characterization of l-tyrosine, which is essential for understanding its role in neurotransmitter synthesis and potential pathological processes. The computed reduction potentials (≈1.27 V) indicate that tyrosine can act as a reducing agent under physiological conditions. The similarity to other neurotransmitters suggests that tyrosine's molecular properties may influence its interactions in neural systems. The finding that the zwitterionic form is more stable in water is consistent with its crystallization behavior and may relate to corneal keratopathy in alkaptonuria patients with hypertyrosinemia. These computational insights could guide future research on tyrosine's involvement in neurodegenerative diseases and its therapeutic applications.