Molecular simulations of zwitterlation-induced conformation and dynamics variation of glucagon-like peptide-1 and insulin

Zwitterionic materials have shown their ability to improve the circulation time and stability of proteins. Zwitterionic peptides present unique potential because genetic technology can fuse them to any wild-type protein. One critical question is the effect of the fusing zwitterionic peptides on the conformation and dynamics of the original protein domain. To shed light on this question, we investigate the conformation and dynamics of six artificial proteins composed of two small therapeutic polypeptide and protein (glucan-like peptide-1 and insulin) and a zwitterionic (glutamic acid-lysine)(10) peptide in an explicit solvent using molecular dynamics simulations. The zwitterionic peptide is fused to the N- and C-terminal of the glucan-like peptide-1 and the chain A and B of the insulin. We analyze the conformation and dynamics variation of the polypeptide and protein domain using root mean square deviation, root mean square fluctuation, solvent accessible surface area, and secondary structure distributions. The simulation results show that the zwitterlation induces substantial changes in the conformation of the glucan-like peptide-1 and a moderate change in the conformation of the insulin, while the two polypeptide and protein remain folded. The glucan-like peptide-1 presents a full alpha-helix conformation when zwitterlated at the C-terminal. The zwitterionic location also plays a role in the conformational change. These zwitterlation-induced conformation variations indicate a comprehensive relationship between zwitterlation and protein stability and activity.