# Employing Metadynamics to Predict the Membrane Partitioning of Carboxy-2H-Azirine Natural Products

## TL;DR

This study uses metadynamics to explore how carboxy-2H-azirine natural products partition into bacterial membranes, revealing their amphipathic behavior.

## Contribution

The paper introduces CHARMM36 parameters for 2H-azirine and uses metadynamics to predict membrane partitioning of carboxy-2H-azirine compounds.

## Key findings

- Carboxy-2H-azirine is strongly hydrophilic, giving long-chain analogs amphipathic properties.
- Long-chain carboxy-2H-azirines partition into bacterial membranes with head groups near the phosphate layer and tails in the membrane.
- Short-chain carboxy-2H-azirines without alkyl tails remain in aqueous solution.

## Abstract

Natural products
containing the carboxy-2H-azirine
moiety are an exciting target for investigation due to their broad-spectrum
antimicrobial activity and new chemical space they afford for novel
therapeutic development. The carboxy-2H-azirine moiety,
including those appended to well-characterized chemical scaffolds,
is understudied, which creates a challenge for understanding potential
modes of inhibition. In particular, some known natural product carboxy-2H-azirines have long hydrophobic tails, which could implicate
them in membrane-associated processes. In this study, we examined
a small set of carboxy-2H-azirine natural products
with varied structural features that could alter membrane partitioning.
We compared the predicted membrane partitioning and alignment of these
compounds to those of established membrane embedders with similar
chemical scaffolds. To accomplish this, we developed parameters within
the framework of the CHARMM36 force field for the 2H-azirine functional group and performed metadynamics simulations
of the partitioning into a model bacterial membrane from aqueous solution.
We determined that the carboxy-2H-azirine functional
group is strongly hydrophilic, imbuing the long-chain natural products
with amphipathicity similar to the known membrane-embedding molecules
to which they were compared. For the long-chain analogs, the carboxy-2H-azirine head group stays within 1 nm of the phosphate
layer, while the hydrophobic tail sits within the membrane. The carboxy-2H-azirine lacking the long alkyl chain instead partitions
completely into aqueous solution.