CryoSHIELDs: tunable amphipathic peptide additives for cryo-EM

Abstract

While cryogenic electron microscopy (cryo-EM) has transformed structural biology, sample preparation remains a major determinant of success. Specifically, the air-water interface (AWI) can damage complexes, impose preferred orientation, and reduce particle density. Here, we introduce cryoSHIELDs, a chemically diverse library of peptide additives designed to passivate the AWI and improve cryo-EM grid preparation. Across 24 protein systems spanning GPCRs, ABC and SLC transporters, soluble and Fab-containing complexes, and enzymes, cryoSHIELDs increased the success rate of structure determination. Individual cryoSHIELDs improved particle density, angular sampling, complex stability, and, for routine targets, map quality and resolution. This toolkit enabled the structural characterization of important targets, including the ABCC6 transporter, revealing unique TMD0-mediated stabilization, and DAMGO-bound -opioid receptor-Gi complex using substantially lower protein concentration. CryoSHIELDs provide a simple, tunable, and broadly applicable platform for more reliable cryo-EM in discovery biology and structure-based drug development.

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BibTeX RIS

BibTeX

@misc{azumaya2026cryoshields,
  title = {{CryoSHIELDs: tunable amphipathic peptide additives for cryo-EM}},
  author = {C. M. Azumaya and P. Dutka and M. C. Johnson and C.-G. Wu and B. D. Delgado and C. W. Koo and J. Y. K. Tom and T. H. Soong and S. K. Ravala and A. Burt and S. Ti and A. C. Howes and O. E. Martinez and A. Song and A. Rohou and C. Ciferri and S. Yatskevich},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.01.755993},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755993v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - CryoSHIELDs: tunable amphipathic peptide additives for cryo-EM
AU  - C. M. Azumaya
AU  - P. Dutka
AU  - M. C. Johnson
AU  - C.-G. Wu
AU  - B. D. Delgado
AU  - C. W. Koo
AU  - J. Y. K. Tom
AU  - T. H. Soong
AU  - S. K. Ravala
AU  - A. Burt
AU  - S. Ti
AU  - A. C. Howes
AU  - O. E. Martinez
AU  - A. Song
AU  - A. Rohou
AU  - C. Ciferri
AU  - S. Yatskevich
PY  - 2026
DA  - 2026/10/01
PB  - bioRxiv
DO  - 10.64898/2026.10.01.755993
UR  - https://www.biorxiv.org/content/10.64898/2026.10.01.755993v1
AB  - While cryogenic electron microscopy (cryo-EM) has transformed structural biology, sample preparation remains a major determinant of success. Specifically, the air-water interface (AWI) can damage complexes, impose preferred orientation, and reduce particle density. Here, we introduce cryoSHIELDs, a chemically diverse library of peptide additives designed to passivate the AWI and improve cryo-EM grid preparation. Across 24 protein systems spanning GPCRs, ABC and SLC transporters, soluble and Fab-containing complexes, and enzymes, cryoSHIELDs increased the success rate of structure determination. Individual cryoSHIELDs improved particle density, angular sampling, complex stability, and, for routine targets, map quality and resolution. This toolkit enabled the structural characterization of important targets, including the ABCC6 transporter, revealing unique TMD0-mediated stabilization, and DAMGO-bound -opioid receptor-Gi complex using substantially lower protein concentration. CryoSHIELDs provide a simple, tunable, and broadly applicable platform for more reliable cryo-EM in discovery biology and structure-based drug development.
ER  -

Abstract

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