How Pegylation Stabilizes a Protein

Abstract

Protein PEGylation has been widely applied by the pharmaceutical industry for making protein drugs with lower immunogenicity, longer circulatory half-life and better bioactivity. However, the efficacy of PEGylation depends on parameters such as attachment site and chain length. Characterizing the relationship between PEGylation pattern and protein stability would therefore be beneficial to designing improved protein PEGylation. Although recent studies have shown that site-specific PEGylation has impact on protein conformation stability and folding rate, there is no clear consensus on how PEGylation stabilizes a protein on the atomistic scale.Through all-atom molecular dynamics simulation, we explored the interaction between the attached PEG oligomer and a β-sheet protein WW domain. While experiments showed clues that stabilizing effect could be attributed to specific interactions between PEG and protein surface residues, a direct correlation cannot be drawn from simulation results. The attached PEG oligomer was flexible and undergoes rapid transitions between extending into the solvent and collapsing onto the protein surface, on a 10 ns time scale. A mechanism including water mediated interaction is therefore suggested.