(577a) Invited: Polymer Stabilization of Peptide Helicies

Helical peptide sequences generally exhibit a greater helical propensity in a protein context than when expressed independently. Mixing helical peptides with synthetic polymers offers the potential for increasing secondary structural stability. In this talk I present our simulation studies of polymer stabilization of helical sequences. In the first half of the talk, I present a preliminary bond fluctuation model simulation study of helix stabilization by polymeric crowding agents. Fitting our simulation results to a Zimm-Bragg-like model for the helix/coil transition, we find the helicies are slightly destabilized by the hydrogen bonding enthalpy despite the fact the crowding polymers exhibit no specific interactions with the peptide. Nevertheless the helix is ultimately entropically stabilized by the reduction of the conformational freedom of the peptide in the coil state.

Rather than using polymer concentration as a tool to stabilize peptide structure, polymer oligomers can be covalently attached to peptides to impart biological activity to synthetic materials. Recently, new amphipathic peptide-poly(ethylene glycol) conjugates were introduced (Shu, J., et al. Biomacromolecules 2008, 9, 2011), which displayed enhanced peptide helicity upon polymer functionalization while retaining tertiary coiled-coil associations. In the second half of this talk, we report simulations of helix stabilization by conjugation with poly(ethylene glycol). The polymer oxygens are shown to favorably interact with the cationic lysine side chains, providing an alternate binding site that protects against disruption of the peptide hydrogen bonds that stabilize the helical conformation. When the peptide lysine charges are neutralized or poly(ethylene glycol) is conjugated with polyalanine, the polymer exhibits a negligible effect on the secondary structure. We also observe the interactions of poly(ethylene glycol) with the amphipathic peptide lysines tends to segregate the polymer away from the nonpolar face of the helix, suggesting no disruption of the interactions that drive tertiary contacts between helicies.