A molecular design approach to peptide drug stabilization

Many peptide drugs are susceptible to chemical degradation. It has been demonstrated experimentally that complexing a polymer to a peptide can prevent its degradation; however, the mechanism behind the stabilizing effect is not known, making it-difficult to design polymers specifically for this purpose. In this work, we have used molecular dynamics experiments to gain insight into the polymer's stabilizing effect. The system AcVYGNGA, a model peptide, which has been extensively studied experimentally, was explored both alone in various forms and complexed with poly(vinylpyrrolidone) (PVP). Results suggest that the peptide-polymer complex must have a secondary structure such that the polymer affects the critical degradation mechanism in two ways: a steric effect based on the polymer's size, and a structural effect by which the physical distance between the reacting atoms within the peptide is increased. These results will be used to develop a set of structure-property relations which can be included within an optimization framework to design new polymers for peptide stabilization.