Effect of Flexibility, Lipophilicity, and the Location of Polar Residues on the Passive Membrane Permeability of a Series of Cyclic Decapeptides

Abstract

Cyclic peptides have received increasing attention over the recent years as potential therapeutics for “undruggable” targets. One major obstacle is, however, their often relatively poor bioavailability. Here, we investigate the structure–permeability relationship of 24 cyclic decapeptides that share the same backbone N-methylation pattern but differ in their side chains. The peptides cover a large range of values for passive membrane permeability as well as lipophilicity and solubility. To rationalize the observed differences in permeability, we extracted for each peptide the population of the membrane-permeable conformation in water from extensive explicit-solvent molecular dynamics simulations and used this as a metric for conformational rigidity or “prefolding.” The insights from the simulations together with lipophilicity measurements highlight the intricate interplay between polarity/lipophilicity and flexibility/rigidity and the possible compensating effects on permeability. The findings allow us to better understand the structure–permeability relationship of cyclic peptides and extract general guiding principles.

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

“…This combination allows straightforward comparison to previous work that was performed in pure water or pure chloroform. 18,21,23,24 We first tested how the CDPs orient towards the interface. Therefore, CDP 1 was placed at the interface in the ‘closed’ and in the major ‘open’ conformation with different orientations and simulated without constraints.…”

“…15,16 To address this issue, many experimental and computational studies have focused on the molecular mechanism of cell permeation of cyclic peptides with the aim to define strategies for the rational design of permeable cyclic peptides. 17–25 N -Methylation of the peptide backbone, change of stereocenters, conformational flexibility, and side-chain modifications can all influence the permeability. Unfortunately, their effect is non-linear and highly site-dependent.…”

“…Unfortunately, their effect is non-linear and highly site-dependent. 24,26–30 The cell permeability of cyclic peptides often drops with increasing peptide size. 31 Nevertheless, some larger cyclic peptides can display internal conformational changes, which are crucial for membrane permeability.…”

“…conformations occurring in both polar and apolar environments, of which the ‘closed’ conformation can be one) facilitate the transition between different environments and therefore increase membrane permeability. 18,21,24 The peptide composition, size, and hydrophobic surface area heavily influence the conformational behaviour of cyclic peptides and thus also the permeability. 21,23,26,27,31 The interplay between all these factors is not trivial to decipher and therefore, it is difficult to establish structure–permeability relationships.…”

“…The conformational and dynamic behavior at these interfaces is hardly understood since previous simulation approaches have focused mainly on homogeneous environments. 21,24 Only few studies have been reported that targeted cyclic peptides in non-homogeneous environments. 39,40 In these studies, biased enhanced sampling approaches were employed to achieve sufficient sampling in the available simulation time.…”