Differential sensing with arrays of de novo designed peptide assemblies

William M Dawson*, Kathryn L Shelley, Jordan M Fletcher, D Arne Scott, Lucia Lombardi, Guto G Rhys, Tania J LaGambina, Ulrike Obst, Antony J Burton, Jessica A Cross, George Davies, Freddie J O Martin, Francis J Wiseman, R Leo Brady, David Tew, Christopher W Wood*, Derek N Woolfson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

10 Citations (Scopus)
49 Downloads (Pure)

Abstract

Differential sensing attempts to mimic the mammalian senses of smell and taste to identify analytes and complex mixtures. In place of hundreds of complex, membrane-bound G-protein coupled receptors, differential sensors employ arrays of small molecules. Here we show that arrays of computationally designed de novo peptides provide alternative synthetic receptors for differential sensing. We use self-assembling α-helical barrels (αHBs) with central channels that can be altered predictably to vary their sizes, shapes and chemistries. The channels accommodate environment-sensitive dyes that fluoresce upon binding. Challenging arrays of dye-loaded barrels with analytes causes differential fluorophore displacement. The resulting fluorimetric fingerprints are used to train machine-learning models that relate the patterns to the analytes. We show that this system discriminates between a range of biomolecules, drink, and diagnostically relevant biological samples. As αHBs are robust and chemically diverse, the system has potential to sense many analytes in various settings.

Original languageEnglish
Article number383
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 24 Jan 2023

Bibliographical note

Funding Information:
We thank Drs. Murray Brown (GSK) and Andy Boyce (Rosa Biotech) for discussions at the early stages of and throughout the project, respectively. W.M.D., J.M.F., G.G.R., L.L., C.W.W. and D.N.W. were funded by a European Research Council Advanced Grant (340764) and a subsequent European Research Council Proof of Concept Grant (787173). J.M.F., L.L. and D.N.W. were also funded by the BBSRC/EPSRC Synthetic Biology Research Centre, BrisSynBio (BB/L01386X/1). G.G.R. was also supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 88899. L.L. and D.N.W. were also supported by the Elizabeth Blackwell Institute, University of Bristol, with funding from the University’s alumni and friends, and a BrisSynBio Flexible Talent Mobility Award (BB/R506539/1). A.J.B., J.A.C., F.J.O.M. were supported by the Bristol Chemical Synthesis Centre for Doctoral Training funded through the EPSRC (EP/G036764). D.A.S. and K.L.S. were supported by the South West Biosciences Doctoral Training Partnership through the Biotechnology and Biological Sciences Research Council (BB/M009122/1). K.L.S., F.J.O.M. and D.N.W. were also supported by the BBSRC (BB/R00661X/1). We thank the University of Bristol School of Chemistry Mass Spectrometry Facility for access to the EPSRC-funded Bruker Ultraflex MALDI-TOF instrument (EP/K03927X/1) and BrisSynBio for access to the BBSRC-funded BMG Labtech Clariostar Plate Reader and Tecan Freedom EVO 150 liquid handling platform (BB/L01386X/1). We would like to thank Diamond Light Source for access to beamlines I04, I04-1 and I24 (Proposal 12342 & 23269), and for the support from the macromolecular crystallography staff.

Funding Information:
We thank Drs. Murray Brown (GSK) and Andy Boyce (Rosa Biotech) for discussions at the early stages of and throughout the project, respectively. W.M.D., J.M.F., G.G.R., L.L., C.W.W. and D.N.W. were funded by a European Research Council Advanced Grant (340764) and a subsequent European Research Council Proof of Concept Grant (787173). J.M.F., L.L. and D.N.W. were also funded by the BBSRC/EPSRC Synthetic Biology Research Centre, BrisSynBio (BB/L01386X/1). G.G.R. was also supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 88899. L.L. and D.N.W. were also supported by the Elizabeth Blackwell Institute, University of Bristol, with funding from the University’s alumni and friends, and a BrisSynBio Flexible Talent Mobility Award (BB/R506539/1). A.J.B., J.A.C., F.J.O.M. were supported by the Bristol Chemical Synthesis Centre for Doctoral Training funded through the EPSRC (EP/G036764). D.A.S. and K.L.S. were supported by the South West Biosciences Doctoral Training Partnership through the Biotechnology and Biological Sciences Research Council (BB/M009122/1). K.L.S., F.J.O.M. and D.N.W. were also supported by the BBSRC (BB/R00661X/1). We thank the University of Bristol School of Chemistry Mass Spectrometry Facility for access to the EPSRC-funded Bruker Ultraflex MALDI-TOF instrument (EP/K03927X/1) and BrisSynBio for access to the BBSRC-funded BMG Labtech Clariostar Plate Reader and Tecan Freedom EVO 150 liquid handling platform (BB/L01386X/1). We would like to thank Diamond Light Source for access to beamlines I04, I04-1 and I24 (Proposal 12342 & 23269), and for the support from the macromolecular crystallography staff.

Publisher Copyright:
© 2023, The Author(s).

Structured keywords

  • Bristol BioDesign Institute
  • BrisSynBio

Keywords

  • Peptides/chemistry
  • Protein Conformation, alpha-Helical
  • Smell

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