Linker, Stephanie, Schellhaas, Christian , Ries, Benjamin , Roth, Hans-Joerg, Fouche, Marianne, Rodde, Stephane and Riniker, Sereina (2022) Polar/Apolar Interfaces Modulate the Conformational Behavior of Cyclic Peptides with Impact on Their Passive Membrane Permeability. RSC advances, 12 (10). pp. 5782-5796.

Abstract

Cyclic peptides have the potential to vastly extend the scope of druggable proteins
and lead to new therapeutics for currently untreatable diseases. However, cyclic pep-
tides often su�er from poor bioavailability. To uncover design principles for permeable
cyclic peptides, a promising strategy is to analyze the conformational dynamics of the
peptides using molecular dynamics (MD) and Markov state models (MSMs). Previous
MD studies have focused on the conformational dynamics in pure aqueous or apolar
environments to rationalize membrane permeability. However, during the key steps of
the permeation through the membrane, cyclic peptides are exposed to interfaces be-
tween polar and apolar regions. Recent studies revealed that these interfaces constitute
the free energy minima of the permeation process. Thus, a deeper understanding of the
behavior of cyclic peptides at polar/apolar interfaces is desired. Here, we investigate
the conformational and kinetic behavior of cyclic decapeptides at a water/chloroform
interface using unbiased MD simulations and MSMs. The distinct environments at the
interface alter the conformational equilibrium as well as the interconversion kinetics of
cyclic peptide conformations. For peptides with low population of the permeable con-
formation in aqueous solution, the polar/apolar interface facilitates the interconversion
to the closed conformation, which is required for membrane permeation. Comparison
to unbiased MD simulations with a POPC bilayer reveals that not only the conforma-
tions but also the orientations are relevant in a membrane system. These �ndings allow
us to propose a permeability model that includes both 'prefolding' and 'non-prefolding'
cyclic peptides - an extension that can lead to new design considerations for permeable
cyclic peptides.

Item Type:	Article
Keywords:	Cyclic peptides, Permeability, Molecular dynamics, conformational behavior
Date Deposited:	03 May 2022 00:45
Last Modified:	03 May 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46518