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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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.
Alkuperäiskielienglanti
LehtiBiochimica et Biophysica Acta. Biomembranes
Vuosikerta1861
Numero11
ISSN0005-2736
DOI - pysyväislinkit
TilaJulkaistu - 31 heinäkuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia

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@article{e12f32c4606e464493dae9031fd852a8,
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",
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.",
keywords = "Bacteria, Antibiotic resistance, Antimicrobial peptide, Lipid membrane, Molecular dynamics simulation, 1182 Biochemistry, cell and molecular biology",
author = "Artturi Koivuniemi and Adyary Fallarero and Alex Bunker",
year = "2019",
month = "7",
day = "31",
doi = "10.1016/j.bbamem.2019.07.016",
language = "English",
volume = "1861",
journal = "Biochimica et Biophysica Acta. Biomembranes",
issn = "0005-2736",
publisher = "Elsevier Scientific Publ. Co",
number = "11",

}

TY - JOUR

T1 - 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

AU - Koivuniemi, Artturi

AU - Fallarero, Adyary

AU - Bunker, Alex

PY - 2019/7/31

Y1 - 2019/7/31

N2 - 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.

AB - 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.

KW - Bacteria

KW - Antibiotic resistance

KW - Antimicrobial peptide

KW - Lipid membrane

KW - Molecular dynamics simulation

KW - 1182 Biochemistry, cell and molecular biology

U2 - 10.1016/j.bbamem.2019.07.016

DO - 10.1016/j.bbamem.2019.07.016

M3 - Article

VL - 1861

JO - Biochimica et Biophysica Acta. Biomembranes

JF - Biochimica et Biophysica Acta. Biomembranes

SN - 0005-2736

IS - 11

ER -