(446b) Modeling the Oxidation of Methionine Residues in Proteins

We report the use of molecular modeling to predict the oxidation propensity of methionine residues in proteins in aqueous solutions by hydrogen peroxide.  Oxidation of methionine to the sulfoxide form is one of the major degradation pathways for therapeutic proteins.  Oxidation can occur during processing or storage of pharmaceuticals and it often reduces or eliminates biological activity.  Identifying the methionines most liable for oxidation may help to overcome the oxidation either through direct mutation or formulation.  We use a molecular model based on atomistic simulations called 2-shell water coordination number (2SWCN) to predict the oxidation rates for several model proteins and therapeutic proteins.  We compare the 2SWCN modeling results against experimental values and with other widely used models that are based on static and simulation average of the solvent accessible area (SAA) for either the side chain or the sulfur atom in the methionine residue.  We find that the 2SWCN model and simulation averaged SAA are highly accurate in predicting the oxidation propensity of methionine residues for the proteins tested.  Thus, the models have sufficient predictive power to enable further protein engineering or to guide formulation approaches to stabilize the unstable methionine residues.