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Chiral lipid bilayers are enantioselectively permeable

Nature Chemistry volume 13, pages 786–791 (2021)Cite this article

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Abstract

Homochiral membrane bilayers organize biological functions in all domains of life. The membrane’s permeability—its key property—correlates with a molecule’s lipophilicity, but the role of the membrane’s rich and uniform stereochemistry as a permeability determinant is largely ignored in empirical and computational measurements. Here, we describe a new approach to measuring permeation using continuously generated microfluidic droplet interface bilayers (DIBs, generated at a rate of 480 per minute) and benchmark this system by monitoring fluorescent dye DIB permeation over time. Enantioselective permeation of alkyne-labelled amino acids (Ala, Val, Phe, Pro) and dipeptides through a chiral phospholipid bilayer was demonstrated using DIB transport measurements; the biological l enantiomers permeated faster than the d enantiomers (from 1.2-fold to 6-fold for Ala to Pro). Enantioselective permeation both poses a potentially unanticipated criterion for drug design and offers a kinetic mechanism for the abiotic emergence of homochirality via chiral transfer between sugars, amino acids and lipids.

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Fig. 1: DIB permeation assay and circuit schematic.
Fig. 2: Fluorescent dye cargo permeation measurements.
Fig. 3: Permeation measurement of alkyne-labelled compounds.
Fig. 4: Permeability measurement of alkyne-labelled dipeptide diastereomers.

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Data availability

Data supporting the findings of this study are available within this article and its Supplementary Information. Raw data of main figures in the article are available from figshare at https://figshare.com/s/b387496fed3d3befd61d.

Code availability

The R code for general data analysis is available from figshare at https://figshare.com/s/b387496fed3d3befd61d.

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Acknowledgements

Funding from the Simons Foundation through the Simons Collaboration on the Origins of Life (SCOL 287625), the National Institutes of Health (R01GM120491) and the National Science Foundation (1255250) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA

    Juan Hu, Wesley G. Cochrane & Brian M. Paegel

  2. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Alexander X. Jones & Donna G. Blackmond

  3. Departments of Chemistry and Biomedical Engineering, University of California, Irvine, CA, USA

    Brian M. Paegel

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  1. Juan Hu
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  2. Wesley G. Cochrane
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  3. Alexander X. Jones
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  4. Donna G. Blackmond
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Contributions

J.H., W.G.C. and B.M.P. conceived the research. J.H. performed the experiments. D.G.B. guided the experimental design related to dipeptides. A.X.J. synthesized and characterized dipeptides. J.H. and B.M.P. analysed the data. All authors wrote the manuscript.

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Correspondence to Brian M. Paegel.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–9, methods and data analysis.

Supplementary Video 1

Droplet generator.

Supplementary Video 2

Droplet synchronizer1_Start.

Supplementary Video 3

Droplet synchronizer2_End.

Supplementary Video 4

Entrance of incubator.

Supplementary Video 5

DIB trains in the incubator.

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Hu, J., Cochrane, W.G., Jones, A.X. et al. Chiral lipid bilayers are enantioselectively permeable. Nat. Chem. 13, 786–791 (2021). https://doi.org/10.1038/s41557-021-00708-z

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