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Exploring Human Mitochondrial Inorganic Pyrophosphatase Functionality: Insights from Molecular Dynamics and Effects of the Deleterious Met94Val Mutation

by Bezpalaya E. | Rodina E. | Vorobyova N. | Kurilova S. | Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia | Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia | A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia | A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia

Abstract ID: 294

Event: BGRS-abstracts

Sections: [Sym 3] Section “Structural biology of proteins nucleic acids and membranes”

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We investigated the functionality of human mitochondrial inorganic pyrophosphatase (hPPA2) and the effects of the Met94Val mutation, which is linked to severe heart conditions. Employing molecular dynamics (MD) simulations, we compared the behavior of wild-type (WT) hPPA2 with the Met94Val pathogenic variant, alongside analogous proteins from thermotolerant yeast (WT and Met52Val OpPPA2). Results indicate conserved stability among all proteins, with mutations altering backbone flexibility, notably in OpPPA2. Analysis also reveals decreased flexibility in active site residues. Principal component analysis (PCA) highlights difference between conformational spaces of WT and Met52Val OpPPA2, but not of human proteins. Met94Val mutation in hPPA2 results in disrupting the anchoring of Tyr142, crucial for substrate binding, potentially leading to mispositioning within the active site.

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