Formation of rippled β-sheets from mixed chirality linear and cyclic peptides—new structural motifs based on the pauling-corey rippled β-sheet
Creators
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1.
University of California, Santa Cruz
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2.
University of California, Los Angeles
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3.
California Institute of Technology
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4.
Korea Advanced Institute of Science and Technology
Abstract
The rippled β-sheet is a structural motif formed by certain racemic peptides that is distinct from the commonly known pleated β-sheet. Although the structure was predicted in 1953, unambiguous crystallographic observation of a rippled β-sheet was not reported until 2022. The structural foundation of the rippled β-sheet field continues to expand, stimulating new research questions, both fundamental and applied. Recent studies found that racemic peptides of varied length and amino acid composition assemble into rippled β-sheets. Intriguingly, certain rippled sheets were found to encapsulate small molecules in ways that could become useful in drug delivery, or to trap harmful substances. These and many other potential applications hinge on the development of a comprehensive structural foundation based on both experiment and theory. In this paper we introduce the concept of the single-component rippled-sheet, composed of joined segments of L and D chirality. The scope of rippled sheet-forming motifs is expanded to include two unexplored classes of rippled sheets: single-component cyclic and linear peptide chimeras. We report on the design, synthesis, and crystal structural characterization of eight self-assembling peptide systems. All five linear systems, in which amino acid sequence, charge and chirality were varied, formed rippled β-sheets with distinct two- and three-dimensional lattices. Of the three cyclic peptides, however, only one system formed a rippled β-sheet, while the other two formed pleated β-sheets. Molecular modeling is used to better understand chiral selection in cyclic systems.
Copyright and License
© 2025 The Author(s). Published by the Royal Society of Chemistry. This article is Open Access. All publication charges for this article have been paid for by the Royal Society of Chemistry.
Contributions
A. H. and J. A. R. designed research; A. H., M. R. S., H. L., M. S. and J. A. R. performed research; A. H., M. R. S., H. L., W. A. G. and J. A. R. analyzed data; A. H., M. R. S.., H. L., M. S., H. K., W. A. G., D. E. and J. A. R. wrote the paper.
Acknowledgement
A. H. and J. A. R. thank the Seaver Institute for a generous gift. We acknowledge the NIH R01AG070895, R01AG048120, RF1AG065407, R01AG074954. We thank the NSF (MCB1616265), and the California NanoSystems Institute at the University of California, Los Angeles. The authors also acknowledge the Department of Energy Grant DE-FC02-02ER63421 for support. This research used beamline 17-ID-2 at the National Synchrotron Light Source II, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704. The Center for BioMolecular Structure (CBMS) is primarily supported by the National Institutes of Health, National Institute of General Medical Sciences (NIGMS) through a Center Core P30 Grant (P30GM133893) and by the DOE Office of Biological and Environmental Research (KP1607011). This work is also based upon research conducted at the Northeastern Collaborative Access Team beamline 24-ID-E, which is funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30GM124165). The Eiger 16M detector is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Duilio Cascio for support during data collection and refinement. WAG thanks NSF (CBET 2311117) and NIH (R01HL155532) for support.
Data Availability
Crystallographic data for [compound number] has been deposited at the PBD under 9DYW, 9DYZ, 9DYY, 9DYZ, 9Z0, 9DZ1, 9N31, and 9N35.
Supplemental Material
Supporting information: d4sc08079c1.pdf
Files
d4sc08079c.pdf
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Additional details
Funding
- National Science Foundation
- MCB1616265
- California NanoSystems Institute
- National Institute of General Medical Sciences
- P30GM133893
- National Institute of General Medical Sciences
- P30GM124165
- Office of Biological and Environmental Research
- KP1607011
- Beatrice and Samuel A. Seaver Foundation
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- National Institutes of Health
- R01AG070895
- National Institutes of Health
- R01AG048120
- National Institutes of Health
- RF1AG065407
- National Institutes of Health
- R01AG074954
- United States Department of Energy
- DE-FC02-02ER63421
- United States Department of Energy
- Office of Science User Facility DE-SC0012704
- Office of Research Infrastructure Programs
- S10OD021527
- Office of Science
- DE-AC02-06CH11357
- National Science Foundation
- CBET 2311117
- National Institutes of Health
- R01HL155532
Dates
- Available
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2025-03-06Published online