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Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers

Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers

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Griffiths, Peter C. ORCID: 0000-0002-6686-1271, Paul, Alison, Apostolovic, Bojana, Klok, Harm-Anton, de Luca, Edoardo, King, Stephen M. and Heenan, Richard K. (2011) Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers. Journal of Controlled Release, 153 (2). pp. 173-179. ISSN 0168-3659 (doi:10.1016/j.jconrel.2011.03.030)

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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 5–10 mol% 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.
© 2011 Elsevier B.V.

Item Type: Article
Additional Information: [1] First available online: 31 March 2011. [2] EPSRC are gratefully acknowledged for the provision of a Platform Grant (EP/C013220/1) (Luca) whilst STFC are thanked for provision of SANS beamtime. This work was supported by the Swiss National Science Foundation and the NCCR Nanoscale Science. [3] Supplementary data to this article can be found online at doi:10.1016/j.jconrel.2011.03.030
Uncontrolled Keywords: coiled-coil motif, peptide delivery, solution conformation, small-angle neutron scattering, endocytosis
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Pre-2014 Departments: School of Science
Related URLs:
Last Modified: 14 Oct 2016 09:23
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
URI: http://gala.gre.ac.uk/id/eprint/9483

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