McCullough, BJ and Kalapothakis, JM and Chin, W and Taylor, K and Clarke, DJ and Eastwood, H and Campopiano, D and MacMillan, D and Dorin, J and Barran, PE (2010) Binding a heparin derived disaccharide to defensin inspired peptides: insights to antimicrobial inhibition from gas-phase measurements. PHYS CHEM CHEM PHYS , 12 (14) 3589 - 3596. 10.1039/b923784d.
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Due to the ubiquitous presence of polysaccharide moieties on bacterial surfaces, it is hypothesised that a peptide-saccharide interaction plays a key role during the recognition of invading microorganisms by beta-defensins. We have employed different gas-phase methods to investigate these interactions. This manuscript describes: an MS-based titration assay measuring the gas-phase binding of ten beta-defensin related peptides to a sulfated disaccharide derived from heparin (HDD); ion mobility-mass spectrometry-determined collision cross sections of 3 peptides (both free and binding HDD); and results from molecular modelling with the aim of reconciling some of our experimental observations. We observe a clear qualitative correlation between the antimicrobial activity of several beta-defensins and related peptides and their gas-phase binding to a heparin-derived disaccharide (HDD). Four of the ten peptides show 4100 micromolar K-d values with HDD, and no bacteriocidal activity, illustrating that HDD binding correlates with peptide antimicrobial activity. For five of the remaining six peptides, bacteriocidal activity was re-measured with HDD present. For the peptides containing intramolecular disulfide bonds in two out of five, bacteriocidal activity was reduced similar to 10-fold; for the remaining three peptides, which lack intramolecular disulfide bonds, HDD addition had little effect on bacteriocidal activity. The latter results are suggested to arise from the greater degree of flexibility imparted by the removal of disulfide bonds giving the peptides the ability to envelope HDD and assume a "defensin-like'' fold. Thus gas-phase analysis is put forward as a powerful tool for assessing the properties of antimicrobial peptides providing valuable insights in the mechanism of antimicrobial inhibition.
|Title:||Binding a heparin derived disaccharide to defensin inspired peptides: insights to antimicrobial inhibition from gas-phase measurements|
|Keywords:||MASS-SPECTROMETRY, PROTEIN COMPLEXES, LIGAND-BINDING, GLYCOSAMINOGLYCANS, BETA-DEFENSIN-3, CONSTANTS, RESISTANT, MEMBRANES, INSERTION, BACTERIA|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry|
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