(140c) Simulation Studies Of Stabilizing Polymers Within Peptide Drug Formulations

The development of novel excipients for stabilization of protein or peptide drugs is a product design and optimization problem which has significant impact on the pharmaceutical industry. Experimental evidence has shown that the polymer poly(vinyl pyrrolidone) (PVP) can greatly decrease the rate of deamidation of the model peptide Ac-VYGGGNGA. In this work, molecular dynamics simulations are employed to model this peptide-polymer system, with the goal of developing structure-property relations for use in product design. Simulation studies using the CVFF force field within the Insight II simulation software were conducted. The distance between one of the reactive oxygen atoms in PVP and the hydroxyl on the tyrosine residue were varied to explore interactions critical to the deamidation rate. Using a ten monomer chain of PVP and the model peptide, this distance was set at values of 1, 1.9, 4, and 10 Å. The system energy was minimized to find the most stable conformations, and then the stability was evaluated. The simulations show that at distances of 1 and 1.9 Å between the two groups (simulating a hydrogen bond), hydrogen bonding occurs between PVP and the peptide at several different sites, including the asparagine group on the model peptide. Bonding at this site is suspected to be key in inhibiting the degradation reaction. This interaction likely causes a significant reduction in the flexibility of the side chain, preventing the asparagine from reacting with the neighboring nitrogen on the glycine backbone (the initial step in the deamidation reaction). The hydrogen bonding could also result in the steric interference from PVP. When the restraint distance is set at 4 Å (not a hydrogen bond), an interesting additional result was observed: the peptide and polymer fold such that the tyrosine residue hydrogen bonds to a different monomer on the polymer. This provides evidence that the hydrogen bonding at the tyrosine residue is critical to the stabilization of the model peptide. The information gained about the stabilization mechanism can be incorporated within a computational molecular design framework to develop excipient polymers with improved functionality.