Análise computacional da interação entre metilmercúrio e as isoformas da apolipoproteína E

Abstract

Methylmercury (MeHg) is one of the most toxic environmental pollutants, accumulating in the central nervous system (CNS) and cardiovascular system, where it promotes oxidative stress, mitochondrial dysfunction, and inflammation. Epidemiological evidence suggests that genetic variability, particularly the different isoforms of Apolipoprotein E (ApoE), influences individual susceptibility to mercury toxicity. The ApoE4 isoform has been associated with greater clinical vulnerability, although the structural mechanisms of this association remain unclear. This study aimed to investigate, using computational methods, potential interactions between CH₃Hg and ApoE isoforms. To this end, geometry optimizations and semiempirical calculations were performed with MOPAC software, in addition to Independent Gradient Model (aIGM) analysis for initial characterization of the interactions. Additionally, the Reduced Density Gradient (RDG) method, implemented in the Multiwfn software, was used to comparatively evaluate the non-covalent interaction (NCI) profiles of ApoE isoforms in the absence and presence of CH₃Hg. The results showed that the ApoE2 and ApoE3 isoforms exhibited greater stability when interacting with MeHg, while ApoE4 was less stable. RDG analyses reinforced these findings, demonstrating that the presence of cysteine residues favors attractive interactions with CH₃Hg, while their absence in ApoE4 results in lower affinity. Thus, the findings of this study reinforce clinical and epidemiological hypotheses that carriers of the ε4 allele are more susceptible to MeHg toxicity because they lack stable protective interactions with the metal. The study provides a basis for understanding how structural variations in ApoE modulate individual susceptibility, highlighting the protein as a relevant genetic biomarker in populations chronically exposed to mercury.