Insight into the antimicrobial mechanism of action of β2,2-amino acid derivatives from molecular dynamics simulation : Dancing the can-can at the membrane surface

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Koivuniemi , A , Fallarero , A & Bunker , A 2019 , ' Insight into the antimicrobial mechanism of action of β2,2-amino acid derivatives from molecular dynamics simulation : Dancing the can-can at the membrane surface ' , Biochimica et Biophysica Acta. Biomembranes , vol. 1861 , no. 11 , 183028 . https://doi.org/10.1016/j.bbamem.2019.07.016

Title: Insight into the antimicrobial mechanism of action of β2,2-amino acid derivatives from molecular dynamics simulation : Dancing the can-can at the membrane surface
Author: Koivuniemi, Artturi; Fallarero, Adyary; Bunker, Alex
Contributor: University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
Date: 2019-11-01
Language: eng
Number of pages: 8
Belongs to series: Biochimica et Biophysica Acta. Biomembranes
ISSN: 0005-2736
URI: http://hdl.handle.net/10138/307588
Abstract: The development of antimicrobial agents that target and selectively disrupt biofilms is a pressing issue since, so far, no antibiotics have been developed that achieve this effectively. Previous experimental work has found a promising set of antibacterial peptides: β2,2-amino acid derivatives, relatively small molecules with common structural elements composed of a polar head group and two non-polar hydrocarbon arms. In order to develop insight into possible mechanisms of action of these novel antibacterial agents, we have performed an in silico investigation of four leading β2,2-amino acid derivatives, interacting with models of both bacterial (target) and eukaryotic (host) membranes, using molecular dynamics simulation with a model with all-atom resolution. We found an unexpected result that could shed light on the mechanism of action of these antimicrobial agents: the molecules assume a conformation where one of the hydrophobic arms is directed downward into the membrane core while the other is directed upwards, out of the membrane and exposed above the position of the membrane headgroups; we dubbed this conformation the “can-can pose”. Intriguingly, the can-can pose was most closely linked to the choice of headgroup. Also, the compound previously found to be most effective against biofilms displayed the strongest extent of this behavior and, additionally, this behavior was more pronounced for this compound in the bacterial than in the eukaryotic membrane. We hypothesize that adopting the can-can pose could possibly disrupt the protective peptidoglycan macronet found on the exterior of the bacterial membrane.
Subject: ATOM FORCE-FIELD
Antibiotic resistance
Antimicrobial peptide
BILAYERS
Bacteria
FLUORESCENCE
HOST-DEFENSE PEPTIDES
Lipid membrane
Molecular dynamics simulation
VALIDATION
1182 Biochemistry, cell and molecular biology
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