Divalent ions as mediators of carbonylation in cardiac myosin binding protein C.

The dosing and efficacy of chemotherapeutic drugs can be limited by toxicity caused by off-pathway reactions. One hypothesis for how such toxicity arises is via metal-catalyzed oxidative damage of cardiac myosin binding protein C (cMyBP-C) found in cardiac tissue. Previous research indicates that metal ion mediated reactive oxygen species induce high levels of protein carbonylation, changing the structure and function of this protein. In this work, we use long timescale all-atom molecular dynamics simulations to investigate the ion environment surrounding the C0 and C1 subunits of cMyBP-C responsible for actin binding. We show that divalent cations are co-localized with protein carbonylation-prone amino acid residues and that carbonylation of these residues can lead to site-specific interruption to the actin-cMyBP-C binding. [Display omitted] • Understanding ion-mediated oxidation of proteins is important to biomanufacturing. • Ion-mediated carbonylation of cardiac thin filament proteins promotes cardiotoxicity. • All-atom molecular dynamics map ion contacts with cardiac myosin binding protein C. • Ions are colocalized with carbonylation-prone residues, identifying "hot spots". • C1 subunit carbonylation potentially interferes with thin filament binding. [ABSTRACT FROM AUTHOR]