Linker chemistry determines secondary structure of p531_4-29 in peptide amphiphile micelles

Biofunctional micelles formed via self-assembly of synthetic peptide-lipid conjugates are a class of promising biomaterials with applications in drug delivery and tissue engineering. The micelle building block, termed, peptide amphiphile, consists of a lipid-Iike chain covalently linked through a spacer to a peptide headgroup. Self-assembly results in formation of a hydrophobic core surrounded by a dense shell with multiple, functional peptides. We report here on the effect that different linkers between a palmitic tail and a bioactive peptide (p53_14-29) have on headgroup secondary structure. Peptide p5314-29 may act as an inhibitor of the interaction between tumor suppressor p53 and human, double minute-2 hDM2 proteins by binding hDM2 in a partially helical form, leading to the release of p53 and the induction of apoptosis in certain tumors. Circular dichroism and fluorescence spectroscopy data revealed that the extent and type of secondary structure of p53_14-29 are controlled through size and hydrogen bond potential of the linker. In addition, the structure of the self-assembled micelles was influenced through linker-dependent altered headgroup interactions. This study provides insight into the mechanisms through which headgroup structuring occurs on peptide amphiphile micelles, with implications on the bioactivity, stability, and morphology of the self-assembled entities.