title: Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers.
abstract: Small-angle neutron scattering and pulsed-gradient spin-echo NMR have been used to examine the solution conformation of a series of water soluble poly(N-(2-hydroxypropyl) methacrylamide) P(HPMA) co-polymer drug delivery vehicles incorporating a coiled-coil peptide motif as a novel pH sensitive non-covalent linker. The conformation of the HPMA homopolymer is well-described by a Gaussian coil model and changing pH from pH 7 to pH 5 has little effect on the solution conformation, as quantified via the radius of gyration. Copolymerisation with 5-10mol% of the K3 peptide bearing methacrylate monomer (K3-MA), gave a series of copolymers that exhibited an increase in radius of gyration at both pH's, despite being typically 30% lower in molecular weight, indicating that the K3-MA causes a perturbation (expansion) of the copolymer conformation. Subsequent addition of an equimolar amount of the complementary peptide E3 makes little further difference to the conformation, indicative of the intimate binding (coiled-coil motif) between the two peptides. Again, the effects of pH are small. Only the addition of a large aromatic structure such as methotrexate causes a further perturbation of the structure - the hydrophobic interaction between the MTX units causes a significant collapse of the polymer coil. These findings further elaborate the understanding of those factors that determine the solution conformation of novel polymer therapeutics.
authors: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, Wales, UK. griffithspc@cardiff.ac.uk
authors: Peter C
authors: PC
authors: Griffiths
authors: Alison
authors: A
authors: Paul
authors: Bojana
authors: B
authors: Apostolovic
authors: Harm-Anton
authors: HA
authors: Klok
authors: Edoardo
authors: E
authors: de Luca
authors: Stephen M
authors: SM
authors: King
authors: Richard K
authors: RK
authors: Heenan
mesh_terms: D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000737:chemistry*; D008968:Molecular Conformation; D033363:Neutron Diffraction; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry*; D011487:Protein Conformation; D053838:Scattering, Small Angle
chemical_list: D008689:Methacrylates; D010455:Peptides; C032802:hydroxypropyl methacrylate