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DECODING PHOSGENE-HEME INTERACTIONS: A DFT STUDY REVEALS Fe-Cl COORDINATION DOMINANCE AND THERAPEUTIC TARGETS
DESCODIFICACIÓN DE LAS INTERACCIONES FOSGENO-HEMO: UN ESTUDIO DFT REVELA LA DOMINANCIA DE LA COORDINACIÓN Fe–Cl Y POSIBLES BLANCOS TERAPÉUTICOS
DOI:
https://doi.org/10.15446/mo.n72.120129Keywords:
phosgene-heme interaction, DFT toxicology, iron-porphyrin binding, chemical warfare antidotes, electronic structure modulation (en)interacción fosgeno-hemo, toxicología DFT, unión hierro-porfirina, antídotos de guerra química, modulación de estructura electrónica (es)
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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.
El fosgeno (COCl₂), un agente altamente tóxico utilizado en la industria y en la guerra química, ejerce sus efectos patológicos mediante interacciones poco comprendidas con proteínas que contienen hemo. Este estudio tiene como propósito dilucidar, a nivel atómico, los mecanismos de unión entre el fosfogeno y el hemo, con el objetivo principal de identificar el modo de coordinación dominante y sus implicaciones en la toxicidad y en la intervención terapéutica. Se empleó teoría del funcional de la densidad (DFT, por sus siglas en inglés), en el nivel B3LYP-D3/6-311+G(d,p) para investigar sistemáticamente la adsorción de fosgeno sobre el hemo (C₂₀H₁₂FeN₄), revelando dos modos de enlace distintos: coordinación Fe(II)-O y Fe(II)-Cl. Nuestros cálculos demuestran que la configuración Fe-Cl es energéticamente más favorable (BE = -4.38 eV/-100.9 kcal.mol-1 a 2.96 Å) frente a la unión Fe-O (1.59 eV/36.6 kcal.mol-1 a 1.55 Å), una preferencia validada mediante comparación con datos de EXAFS (Fe-Cl ∼2.90-3.10 Å) y espectros ópticos experimentales. La dependencia angular identificada muestra una reducción drástica de la energía de enlace (-8.83 eV) por encima de los 80° de rotación, mientras que los efectos del disolvente (agua, etanol) debilitan la unión Fe-O en un ∼25%, correlacionándose con la atenuación observada de la toxicidad dependiente de la humedad. La modulación mediante campo eléctrico (0.01 au) reduce la energía de enlace Fe-Cl en un 10%, lo que sugiere estrategias novedosas de desintoxicación. Las simulaciones de espectros UV-Vis reproducen los desplazamientos característicos de la banda de Soret (Δλ = 22 nm) observados en la hemoglobina expuesta al fosgeno, estableciendo un marco computacional para predecir efectos toxicológicos. Estos hallazgos proporcionan: (1) la primera explicación a nivel atómico de la selectividad del fosgeno por el hemo, (2) relaciones cuantitativas entre estructura y toxicidad para el desarrollo de antídotos, y (3) una metodología validada para estudiar interacciones entre gases tóxicos y biomoléculas. Este trabajo conecta la química computacional con la defensa biomédica, ofreciendo perspectivas mecanicistas que orientan el diseño de intervenciones terapéuticas contra amenazas químicas.
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