Lasso peptides feature a cyclic moiety and “tail” that form a unique lariat-knot topology. The flexibility and durability of this topology shows potential in bio- and chemical engineering applications, mainly as a molecular “switch” and a foundational monomer for dynamic covalent supramolecular structures. For example, equilibrium concentrations of the multiple conformers of lasso peptide benenodin-1 can be modulated by temperature. However, the mechanical and chemical characteristics governing the lasso peptide’s topology, especially the steric “plugs” that lock the tail within the cyclic moiety, are largely unknown. In this talk, we will discuss the development of a multiscale quantum mechanics/molecular mechanics (QM/MM) protocol to evaluate the thermodynamic and kinetic parameters of lasso peptide switch. We will describe the application of the protocol in a ring-thread model system derived from lasso peptide astexin-3 (Ast-3) ring. The results of this study provide valuable leads towards rational design of lasso peptides for bio- and chemical engineering purposes.

Untying the knot: Multiscale simulations of lasso peptide switch

ACS Spring 2022

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