Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products DOI Creative Commons
Clyde A. Daly, Leah M. Seebald,

Emma Wolk

et al.

Published: April 16, 2024

Natural products have diverse chemical structures and biological activities which often serve as sources of new therapeutic agents. Those containing a carboxy-2H-azirine moiety are an exciting target for investigation due in part to the broad-spectrum antimicrobial activity these compounds significant space novel development offered by this unique scaffold. The moiety, including those appended well-characterized scaffolds, is understudied, creates challenge understanding potential modes inhibition. In particular, some known natural product carboxy-2H-azirines long hydrophobic tails, might lead amphipathicity implicate them membrane associated processes. Metadynamics effective method calculating free energy changes with embedding study, we examined small set products, analogs alkyl chains, geometric isomers, one comprising simple core. We compared physiochemical properties established embedders similar scaffolds. This was intended isolate group understand molecular influences on partitioning. To accomplish this, developed force field 2H-azirine functional performed metadynamics simulations partitioning into model (75 % POPE, 25 POPG) from aqueous solution. determine that likely hydrophilic, imbuing chain binding molecules they were compared. For analogs, headgroup stays within 1 nm phosphate layer, while lacking partitions completely

Language: Английский

Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products DOI Creative Commons
Clyde A. Daly, Leah M. Seebald,

Emma Wolk

et al.

Published: April 16, 2024

Natural products have diverse chemical structures and biological activities which often serve as sources of new therapeutic agents. Those containing a carboxy-2H-azirine moiety are an exciting target for investigation due in part to the broad-spectrum antimicrobial activity these compounds significant space novel development offered by this unique scaffold. The moiety, including those appended well-characterized scaffolds, is understudied, creates challenge understanding potential modes inhibition. In particular, some known natural product carboxy-2H-azirines long hydrophobic tails, might lead amphipathicity implicate them membrane associated processes. Metadynamics effective method calculating free energy changes with embedding study, we examined small set products, analogs alkyl chains, geometric isomers, one comprising simple core. We compared physiochemical properties established embedders similar scaffolds. This was intended isolate group understand molecular influences on partitioning. To accomplish this, developed force field 2H-azirine functional performed metadynamics simulations partitioning into model (75 % POPE, 25 POPG) from aqueous solution. determine that likely hydrophilic, imbuing chain binding molecules they were compared. For analogs, headgroup stays within 1 nm phosphate layer, while lacking partitions completely

Language: Английский

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