TITLE:
Tunable Energetic Stabilization Governs Self- and Mixed-Aggregation of Möbius and Bracelet Cyclotides
AUTHORS:
Nithikumar R. Yadav, Eric N. Njabon, Issofa Patouossa, Neville Y. Forlemu
KEYWORDS:
Cyclotides, Molecular Dynamics Simulations, Peptide Aggregation, Non-Bonded Interactionsm Self-Assembly
JOURNAL NAME:
Computational Chemistry,
Vol.14 No.2,
March
20,
2026
ABSTRACT: The environmental persistence and off-target toxicity of conventional synthetic pesticides continue to motivate the development of sustainable, biologically derived alternatives. Cyclotides—plant-derived, backbone-cyclized peptides stabilized by a cystine-knot motif—are promising candidates due to their exceptional chemical stability and intrinsic insecticidal and antimicrobial activities. However, the molecular determinants governing cyclotide aggregation, which directly affect formulation stability and bioavailability, remain insufficiently understood. Here, atomistic molecular dynamics simulations in explicit solvent were used to investigate self-aggregation and mixed-composition assembly of representative Möbius and Bracelet cyclotides across multiple concentrations. Time-resolved analyses of total potential, van der Waals (vdW), and Coulombic energies were employed as quantitative descriptors of stability. Aggregation occurred rapidly in all systems, with energies converging to stable equilibrium plateaus. Although statistically significant differences in equilibrium energies were observed as a function of peptide composition and concentration (p