Insights into How Cyclic Peptides Switch Conformations

Abstract

Cyclic peptides have recently emerged as promising modulators of protein-protein interactions. However, it is currently highly difficult to predict the structures of cyclic peptides owing to their rugged conformational free energy landscape, which prevents sampling of all thermodynamically relevant conformations. In this article, we first investigate how a relatively flexible cyclic hexapeptide switches conformations. It is found that, although the circular geometry of small cyclic peptides of size 6-8 may require rare, coherent dihedral changes to sample a new conformation, the changes are rather local, involving simultaneous changes of ϕi and ψi or ψi and ϕi+1. The understanding of how these cyclic peptides switch conformations enables the use of metadynamics simulations with reaction coordinates specifically targeting such coupled two-dihedral changes to effectively sample cyclic peptide conformational space.