A molecular simulation approach to peptide stabilization

Experiments carried out by Topp and Sinha (2006) found that the polymer poly(vinylpyrrolidone) prevented the peptides AcVYGNGA and AcVYGGGNGA from undergoing a self-degrading deamidation reaction. In this work, molecular simulation was used to gain insight into the mechanism of action of the stabilizing effect of polymers on peptides. Two possible pathways of stabilization were identified. In the first, the amino hydrogen atoms of the asparagine side chain hydrogen bond with the oxygen atoms of the polymer, preventing the asparagine from reacting with its neighboring glycine backbone nitrogen, an initial step in the degradation reaction. In the second, the conformational effect of the polymer on the peptide results in the asparagine side chain forming hydrogen bonds with the tyrosine side chain, preventing its ability to react with the backbone nitrogen. It was also found that the two additional glycine residues in AcVYGGGNGA affect the peptide's secondary structure in such a way that the asparagine is brought into closer proximity to the tyrosine residue. This result supports the experimental findings that AcVYGGGNGA is better stabilized by PVP than AcVYGNGA, and supports both stabilizing pathways. If the asparagine is closer to the tyrosine, where PVP is assumed to bind in the first pathway, the asparagine side chain can more readily hydrogen bond with the polymer. In the second pathway, the decreased distance would allow the asparagine side chain to interact more strongly with the tyrosine side chain. The results from this work provide valuable insight into the stabilizing effect of poly(vinylpyrrolidone) on AcVYGNGA and AcVYGGGNGA. Understanding the underlying mechanisms of stabilization will allow improved polymers to be designed for peptide stabilization.