Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116755
Title: Control of Peptide Aggregation and Fibrillation by Physical PEGylation
Authors: Ambrosio, Elena
Podmore, Adrian
Gomes Dos Santos, Ana L
Magarkar, Aniket
Bunker, Alex
Caliceti, Paolo 
Mastrotto, Francesca 
van der Walle, Christopher F
Salmaso, Stefano 
Keywords Plus: VASOACTIVE-INTESTINAL-PEPTIDE;MOLECULAR-DYNAMICS SIMULATION;CIRCULAR-DICHROISM;PROTEIN AGGREGATION;THIOFLAVIN-T;PEG-CHOLANE;MODEL;DELIVERY;INSULIN;TEMPERATURE
Mesh headings: Cholanes;Palmitic Acid;Polyethylene Glycols;Polymers;Vasoactive Intestinal Peptide
Secondary Mesh headings: Humans;Lipoylation;Protein Conformation
Issue Date: 2018
Publisher: AMER CHEMICAL SOC
Journal: Biomacromolecules 
Abstract: 
Peptide therapeutics have the potential to self-associate, leading to aggregation and fibrillation. Noncovalent PEGylation offers a strategy to improve their physical stability; an understanding of the behavior of the resulting polymer/peptide complexes is, however, required. In this study, we have performed a set of experiments with additional mechanistic insight provided by in silico simulations to characterize the molecular organization of these complexes. We used palmitoylated vasoactive intestinal peptide (VIP-palm) stabilized by methoxy-poly(ethylene glycol)5kDa-cholane (PEG-cholane) as our model system. Homogeneous supramolecular assemblies were found only when complexes of PEG-cholane/VIP-palm exceeded a molar ratio of 2:1; at and above this ratio, the simulations showed minimal exposure of VIP-palm to the solvent. Supramolecular assemblies formed, composed of, on average, 9-11 PEG-cholane/VIP-palm complexes with 2:1 stoichiometry. Our in silico results showed the structural content of the helical conformation in VIP-palm increases when it is complexed with the PEG-cholane molecule; this behavior becomes yet more pronounced when these complexes assemble into larger supramolecular assemblies. Our experimental results support this: the extent to which VIP-palm loses helical structure as a result of thermal denaturation was inversely related to the PEG-cholane:VIP-palm molar ratio. The addition of divalent buffer species and increasing the ionic strength of the solution both accelerate the formation of VIP-palm fibrils, which was partially and fully suppressed by 2 and >4 mol equivalents of PEG-cholane, respectively. We conclude that the relative freedom of the VIP-palm backbone to adopt nonhelical conformations is a key step in the aggregation pathway.
URI: http://hdl.handle.net/20.500.12857/116755
ISSN: 15257797
DOI: 10.1021/acs.biomac.8b00887
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