1 Department of Chemistry, University of Prince Edward Island, Charlottetown C1A 4P3, Prince Edward Island, Canada.
2 Department of Chemistry and Biochemistry, Concordia University, Montreal H4B 1R6, Quebec, Canada.
3 Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax B3H 4R2, Nova Scotia, Canada.
4 Department of Chemistry, Dalhousie University, Halifax B3H 4R2, Nova Scotia, Canada.
5 School of Biomedical Engineering, Dalhousie University, Halifax B3H 4R2, Nova Scotia, Canada.
6 Département de Chimie, Université de Montréal, 1375 Ave. Thérèse-Lavoie-Roux, Montréal H2 V 0B3, Québec, Canada.
7 Department of Chemical and Materials Engineering, Concordia University, Montreal H4B 1R6, Quebec, Canada.
8 Faculty of Sustainable Design Engineering, University of Prince Edward Island, Charlottetown C1A 4P3, Prince Edward Island, Canada.

Lactam cross-links have been employed to stabilize the helical secondary structure and enhance the activity and physiological stability of antimicrobial peptides; however, stabilization of ß-sheets via lactamization has not been observed. In the present study, lactams between the side chains of C- and N-terminal residues have been used to stabilize the ß-sheet conformation in a short ten-residue analogue of chicken angiogenin-4. Designed using a combination of molecular dynamics simulations and Markov state models, the lactam cross-linked peptides are shown to adopt stabilized ß-sheet conformations consistent with simulated structures. Replacement of the peptide side-chain Cys-Cys disulfide by a lactam cross-link enhanced the broad-spectrum antibacterial activity compared to the parent peptide and exhibited greater propensity to induce proinflammatory activity in macrophages. The combination of molecular simulations and conformational and biological analyses of the synthetic peptides provides a useful paradigm for the rational design of therapeutically active peptides with constrained ß-sheet structures.