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Published May 28, 2025 | Published
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Design Guidelines to Control Rippled β-Sheets versus Pleated β-Sheets in Mixed-Chirality Peptides

Lee, Hyeonju1, 2
Hazari, Amaruka3
Raskatov, Jevgenij A.3 ORCID icon
Kim, Hyungjun1, 2 ORCID icon
Goddard, William A., III2 ORCID icon
  • 1. ROR icon Korea Advanced Institute of Science and Technology
  • 2. ROR icon California Institute of Technology
  • 3. ROR icon University of California, Santa Cruz

Abstract

Decoding how amino acid sequences determine structure facilitates the design of functional proteins, advanced biomaterials, and selective, low-side-effect drugs. The rippled β-sheet, theorized by Pauling and Corey in 1953, has only recently begun to gain experimental support. However, research on rippled β-sheets remains limited, leaving gaps in our understanding of when and how they occur. To understand the relationship between sequences and rippled β-sheet formation propensities, we carried out molecular dynamics (MD) and density functional theory (DFT) simulations to predict the energetics for six systems of forming either a rippled or pleated β-sheets that are ordered either parallel or antiparallel. Notably, among these four possible structures of each system, the structure predicted to have the lowest energy agrees with the single case observed experimentally! To understand why this form is favored, we investigate the local structures of all six systems, with particular attention to the role of hydrogen bonds (H-bonds) in stabilization. In each system, the peptide consistently adopts a motif that allows it to form the maximum number of H-bonds between backbones, even when amidated, and composed of a single-component with mixed chirality or a cyclic peptide. We find that an achiral glycine-glycine bridge acts as a spacer between valine residues, effectively reducing steric hindrance between side chains. Furthermore, we conclude that the structures of cyclic peptides are stabilized by intramolecular H-bonds in an anhydrous environment. Our findings provide deeper insights into how sequences influence β-sheet conformations, enabling us to propose guidelines for the preferred structures of novel peptides.

Copyright and License

Copyright © 2025 American Chemical Society

Supplemental Material

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c16425.

  • Number of atoms and molecules of all systems (Table S1); initial structure for all systems (Figures S1 and S2); lattice parameter of supercells from MD simulation and X-ray crystallography with error (Table S2); RMSD information for all systems (Figures S3–S5); local structures of AR and PP for [VVGgvv-NH2]n (Figure S6); average dihedral angles for third and fourth Gly or Ala residues of L- and D-peptide in [VVGGVV:vvggvv]n, [VVAAVV:vvaavv]n, [VVGGVV-NH2:vvggvv-NH2]n, [VVAAVV-NH2:vvaavv-NH2]n, [VVGgvv-NH2]n, and [VVAavv-NH2]n compared with experiment data just for Gly residue (Table S3); final snapshot, CED, and number of H-bonds in [VVAAVV:vvaavv]n, [VVAAVV-NH2:vvaavv-NH2]n, and [VVAavv-NH2]n (Figure S7); local structure of [VVGGVV:vvggvv]n, [VVAAVV:vvaavv]n, [VVGGVV-NH2:vvggvv-NH2]n, [VVAAVV-NH2:vvaavv-NH2]n, [VVGgvv-NH2]n, and [VVAavv-NH2]n. Figure S9 shows local structure of cyclic peptide in [cyclic VVGGVVGG]n, and [cyclic VVGGvvgg]n (Figure S8); how to construct PR, AP, and AR structures of [cyclic VVGGvvgg]2 and [cyclic FKFGGfefgg]2 (Figures S10 and S14); final snapshots for anhydrous [cyclic VVGGvvgg]n of PP, PR, AP, and AR structures (Figure S11); local structure of cyclic VVGGvvgg for the solvated and anhydrous system (Figure S12); probability of detecting water molecules within [cyclic FKFGGfefgg]n and [cyclic VVGGvvgg]n (Figure S13); final snapshots of AR, AP, PR, and PP of [cyclic FKFGGfefgg]n, CED, and number of H-bond (Figure S15); initial system of PP, PR, AP, and AR of [NNGgnn]8, [QQGgqq]8, [NNGgqq]8, and [NQGgqn]8 (Figure S16); number of H-bonds in [NNGgnn]8, [QQGgqq]8, [NNGgqq]8, and [NQGgqn]8 (Table S4); scheme of the one-residue shift in the antiparallel pleated arrangement in terms of the top and side views and the top view of the antiparallel rippled β-sheet (Figure S17) (PDF)

Conflict of Interest

The authors declare no competing financial interest.

Acknowledgement

WAG thanks NIH (R01HL155532) and NSF (CBET 2311117) for the financial support. H.L. and H.K. acknowledge the support by the National Research Foundation of Korea grants funded by the Korea government (RS-2024-00405261 and RS-2024-00351536). Prof. Xiao Wang is gratefully acknowledged for helpful comments on the paper.

Additional details

Funding Dates Caltech Custom Metadata
Created:
July 23, 2025
Modified:
July 23, 2025