Vol. 24, No. 1 (2025), Sim24364 https://doi.org/10.24275/rmiq/Sim24364

Arsenate modulation of CYP2C8 heteroenzime electronic properties: An evaluation from density functional theory

 

Authors

P.G. Nieto-Delgado, J.G. Rodríguez-Zavala, A.A. Vértiz-Hernández, J.D. Sánchez-Vásquez

Abstract

This study investigates the structural, electronic, and spin polarization properties of different molecular models of the CYP2C8 enzyme, focusing on the effects of arsenate (AsO43-) binding to the heme group. Using density functional theory (DFT) calculations, we explored the interactions between arsenate and the iron (Fe) center of the heme group across three models with varying amino acid compositions. Despite structural variations, the charge density and polarization properties remained consistent across models. In the absence of arsenate, the heme group exhibited a dipolar moment with Fe showing a charge of approximately -0.12e and cysteine 435 sulfur (S) having a charge of 0.28e. Strong positive polarization was observed in Fe (1.77 μB), while S showed a smaller polarization (~0.19 μB). Upon arsenate introduction, AsO43- bonded with the Fe center, especially in smaller amino acid models, with the As-Fe bond distance optimized to 3.3–3.4 Å. The presence of arsenate reduced the charge on the sulfur atom to approximately 0.17e, significantly decreasing the Fe-S dipolar moment. Additionally, the Fe polarization slightly decreased (to 1.65–1.67 μB), and the sulfur polarization became almost negligible (~0.01 μB). The oxygen atoms of the arsenate showed negative spin polarization (up to -0.43 μB), altering the system’s electronic properties. These results suggest that arsenate binding induces notable changes in the enzyme's electronic environment, potentially affecting its physiological role.

Keywords

Arsenate ions, heme-iron center, CYP2C8 enzyme, drug metabolism, DFT.

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