Effect of 4-HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with β-Spectrin: A Molecular Dynamics Simulation Study

4-HNE-modified ankyrins have been described in diseases such as diabetes, renal failure, G6PD deficient, sickle cell trait, and P. falciparum infected erythrocytes with different ABO blood groups. However, effects at the atomic level of this carbonylation on structure and function of modified protein are not yet fully understood. We present a study based on molecular dynamics simulations of nine 4-HNE modified residues of the ZUS-ANK ankyrin domain with beta-spectrin and their binding energy profiles. Results show that 4-HNE induced local conformational changes over all protein systems evaluated, increased mobility in the modification sites, and localized structural changes between the positively charged patch of the ZUS-ANK domain. Carbonylation with 4-HNE on lysine residues decreased the affinity between ZU5-ANK and the 14-beta-spectrin repeat by reducing electrostatic and van der Waals interactions. The presented work provides further insight into understanding the loss of human erythrocyte deformation capacity under conditions of oxidative stress in different diseases.