DESCODIFICACIÓN DE LAS INTERACCIONES FOSGENO-HEMO: UN ESTUDIO DFT REVELA LA DOMINANCIA DE LA COORDINACIÓN Fe–Cl Y POSIBLES BLANCOS TERAPÉUTICOS

Phosgene (COCl₂), a highly toxic industrial and chemical warfare agent, exerts its pathological effects through poorly understood interactions with heme-containing proteins. The essence of this study lies in elucidating the atomic-level mechanisms of phosgene-heme binding, with the primary objective of identifying the dominant coordination mode and its implications for toxicity and therapeutic intervention. This study employs density functional theory (DFT) at the B3LYP-D3/6-311+G(d,p) level to systematically investigate phosgene adsorption on heme (C₂₀H₁₂FeN₄), revealing two distinct binding modes: Fe(II)-O and Fe(II)-Cl coordination. Our calculations demonstrate that the Fe-Cl configuration is energetically favored (BE = -4.38 eV/-100.9 kcal/mol at 2.96 Å) over Fe-O binding (1.59 eV/36.6 kcal/mol at 1.55 Å), a preference validated by comparison with EXAFS data (Fe-Cl ∼2.90-3.10 Å) and experimental optical spectra. The identified angular dependence shows catastrophic binding energy reduction (-8.83 eV) beyond 80° rotation, while solvent effects (water, ethanol) weaken Fe-O binding by ∼25%, correlating with observed humidity-dependent toxicity attenuation. Electric field modulation (0.01 au) reduces Fe-Cl binding energy by 10%, suggesting novel detoxification strategies. UV-Vis spectral simulations reproduce the characteristic Soret band shifts (Δλ = 22 nm) observed in phosgene-exposed hemoglobin, establishing a computational framework for predicting toxicological outcomes. These findings provide: (1) the first atomic-level explanation of phosgene's heme-binding selectivity, (2) quantitative structure-toxicity relationships for antidote development, and (3) a validated methodology for studying related toxic gas-biomolecule interactions. The work bridges computational chemistry and biomedical defense, offering mechanistic insights to guide therapeutic interventions against chemical threats.