Molecular Dynamics Simulation Study on the Stabilization of Interferon-α2a Protein by Poly(ethylene glycol) and Polysarcosine

Interferon-α2a (IFN-α2a), a cell-signaling therapeutic protein, is effective in treating diseases such as cancer and hepatitis. However, their clinical application is limited by rapid degradation and clearance from the body. PEGylation improves its stability and in vivo circulation time but raises concerns over immunogenicity and poor biodegradability. Polysarcosine (PSar), a biodegradable and biocompatible polypeptoid with PEG-like solubility, reduced immune recognition, and tunable properties, presents a promising alternative to PEG. We present here all-atom molecular dynamics (MD) simulations demonstrating that the interactions and stabilizing effects of polysarcosine (PSar) are similar to those of poly(ethylene glycol) (PEG) on IFN-α2a. Both polymers preserve the native protein fold across concentrations, with PSar producing a lower root-mean-square deviation (RMSD) of protein residues from their reference configurations than does PEG. Both polymers suppress hydrogen bonding of the protein with water by up to 10% at polymer concentrations typically produced by PEGylation, while creating similarly large numbers of polymer contacts with IFN-α2a, mostly, but not exclusively, with polar residues, suggesting that PSar is likely just as effective as PEG in preventing IFN-α2a aggregation. These atomistic insights highlight the enhanced ability of PSar to retain the structural stability of IFN-α2a, shielding it against aggregation as well as does PEG, reinforcing its potential as a next-generation, nonimmunogenic alternative to PEG for therapeutic protein stabilization.