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Title: Structure and activity of antimicrobial peptoids
Author: Woodhouse, Vanessa Jane
ISNI:       0000 0004 9355 2137
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2020
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This thesis concerns complementary experimental and computational investigations into the relationship between the primary sequence and secondary structure of peptoids. Peptoids are a class of peptide mimetic molecules with applications as novel antimicrobial agents. The antimicrobial properties of peptoids are linked to their interactions with lipid bilayers in cell membranes, which in turn are linked to their helical secondary structure, making understanding sequence to structure relationships crucial to the design of functional sequences. Here we investigate a library of linear, cationic peptoid sequences with structural variations in the proportion and positioning of helix inducing residues and the chemical nature of the cationic side chains. We use circular dichroism spectroscopy to characterise the peptoids in aqueous and organic solvent and also to investigate structural changes upon binding to lipid bilayers designed to mimic mammalian and bacterial membranes. We present a new set of force field parameters, derived from GAFF and quantum mechanical calculations, that accurately capture the backbone torsional preferences of peptoids. Subsequently we use the modified force field to perform atomistic MD simulations of our library of peptoid sequences, using Hamiltonian replica exchange to improve sampling at less computational expense than traditional replica exchange methods. The CD spectra reveal that the peptoids adopt characteristically helical secondary structures with variations depending on primary sequence. The intensity of helical features increases upon increasing the proportion of helix inducing residues, switching from an aqueous to an organic environment and as extra methylene groups are added to the cationic side chains, increasing their length. The length and proportion of cationic side chains also influences the folded hydrophobicity of the peptoids, though this does not correlate to their antimicrobial activity. Modelling the binding of the peptoids to lipids as a two state system enables us to estimate, in some cases, the free energy of transfer into the bilayer, where the length of the cationic side chain is also influential. MD simulations do not reveal a clear distinction in peptoid backbone conformation depending on cationic side chain length however it is clear that the peptoid backbone is more flexible and deviates more from a perfect helical conformation in aqueous than organic solvent. Ultimately these findings may aid in the rational design of new sequences.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available