Molecular dynamics simulation of the conformational mobility of the lipid-binding site in the Apolipoprotein E isoforms ε2, ε3, and ε4

Neurodegenerative disorders, particularly Alzheimer’s disease, have become a major healthcare issue all over the world. Despite extensive research, the molecular mechanisms underlying these conditions are yet to be identified. APOE is the apolipoprotein E-coding gene. Its polymorphisms have been found to be significantly associated with both neurodegenerative disorders (rs429358, C112R) and protective effects against these disorders (rs7412, R158C). Humans carry three apolipoprotein E isoforms: ε2 (protein with a protective mutation), ε3 (wild-type protein), and ε4 (protein with a pathogenic mutation). The study sought to investigate how these substitutions affect the lipid-binding site, which is the functional region of the protein. Molecular dynamics simulation was used to analyze all three isoforms. We found that, unlike the wild-type isoform, both the pathogenic and protective mutations caused changes in the lipid-binding site. The changes, however, were different. Both ε2 and ε4 lead to an increased distance between the N-terminal (amino acids 88-104) and the C-terminal (amino acids 251-266) helices. However, in ε2, the C-terminal helix retained its structure, whereas in ε4, it unwound between amino acids 260 and 266. The opposite was true for the N-terminal helix. It is safe to assume that it is these structural differences in the lipid-binding site that account for the different effects of these two isoforms and clinical characteristics of their carriers. The clustering analysis allowed for the identification of the structures, most typical of ε2 and ε4, which could be used as the foundation for further molecular dynamics studies.

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