Membrane-like interfaces can facilitate the conformational closure of cyclic peptides for passive membrane permeability

Cyclic peptides have the potential to vastly extend the scope of druggable proteins and to lead to new therapeutics for currently untreatable diseases. However, the design of cyclic peptides with oral bioavailability is challenging and often only achieved via a tedious trial-and-error process. We use molecular dynamics (MD) simulations and Markov state modeling of cyclic peptides to rationalize the relationship between their structure and passive membrane permeability. Previous work has shown that an important determinant for permeability is a peptide's conformational behavior in different environments.