Tackling APOE's structural challenges via in silico modeling in the era of neural networks: Can AlphaFold II help circumvent the problem of lacking full-length protein structure?

Tackling APOE's structural challenges via in silico modeling in the era of neural networks: Can AlphaFold II help circumvent the problem of lacking full-length protein structure?

The APOE gene, encoding apolipoprotein E, is a predictor of longevity and age-related diseases. Despite numerous genetic studies, the data on molecular mechanisms by which apolipoprotein E affects the human phenotype remain incomplete due to the structural properties of the protein. Recently, a numb...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics Vol. 761; p. 110185
Main Authors: Mamchur, A.A., Ivanov, M.V., Matkava, L.R., Yudin, V.S., Keskinov, A.A., Yudin, S.M., Kashtanova, D.A.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-11-2024
Subjects:
AlphaFold II
APOE
In silico drug design
Longevity
Molecular dynamics
Thermal stability
Molecular dynamics
APOE
Longevity
AlphaFold II
In silico drug design
Thermal stability
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Summary:The APOE gene, encoding apolipoprotein E, is a predictor of longevity and age-related diseases. Despite numerous genetic studies, the data on molecular mechanisms by which apolipoprotein E affects the human phenotype remain incomplete due to the structural properties of the protein. Recently, a number of studies have used in silico drug discovery techniques based on protein-ligand docking, further highlighting the issue of lacking 3D structure of apolipoprotein E. Using molecular dynamics simulation, we found that AlphaFold II models of apolipoprotein E conformationally significantly differ both from the only available NMR structure, 2L7B, and structures obtained through circular dichroism spectroscopy: the ε4 isoform lacks the salt bridge between R61 and E255, while the ε2 and ε3 isoforms have extensive networks of interdomain interactions. Our findings challenge the benefits of using AlphaFold II for obtaining starting conformations for molecular docking. •APOE is associated with many aging-associated phenotypes.•Incomplete data on these associations is due to the protein's structural properties.•A well-defined APOE structure would facilitate drug discovery.•AlphaFold II APOE models differ significantly from NMR and CD spectroscopy data.•AlphaFold-based molecular docking for drug discovery may not offer the desired benefits.
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ISSN:0003-9861
1096-0384
1096-0384
DOI:10.1016/j.abb.2024.110185