4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study

4-hydroxy-2-nonenal (4-HNE) is the main end product of peroxidation in lipids, capable of introduce carbonyl groups to nucleophilic amino acids via Michael additions and alter protein function. It has been reported that 4-HNE protein carbonylation is associated with intracellular protein aggregation, the pathogenesis of neurodegenerative and metabolic diseases and yet it is unclear how the carbonylation affects the protein structure and dynamics at the atomic level. Here, we analysis the structural effects of 4-HNE modification through formation of Michael adducts of Cys-4HNE, His-4HNE and Lys-4HNE on Serum Albumin (BSA) and Thioredoxin (TRX). Since both proteins have experimental evidence to possess 4-HNE-modifications on cysteine, histidine and lysine residues, extended molecular dynamics simulations were performed with AMBER to study the carbonylation effects in the structure of these proteins. BSA is the main protein of plasma while TRX is an important antioxidant enzyme. Results showed local changes and alteration in the conformational stability, folding and flexibility after including the 4-HNE modification. DSSP analysis showed important structural modifications as a consequence of the inclusion of the modified residues. Analysis of the computed trajectories suggests that 4-HNE decreases stability, increases local flexibility and produced modest unfolding on both tested proteins. Finally, all the systems evaluated shown an increase in the lipophilic potential and a modest decrease in the electrostatic potential in BSA but an increase in TRX. (C) 2018 Elsevier Inc. All rights reserved.