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

Abstract

This study uses molecular dynamics and Markov state models to analyse how interfaces interact with cyclic decapeptides and modulate their dynamic and equilibrium properties.

Conformational Effects on the Passive Membrane Permeability of Synthetic Macrocycles

“…Molecular dynamics simulations by the Akiyama group showed that cyclic peptides with low or moderate lipophilicity tend to interact favorably at the head-group region of the membrane, where their polar groups have contact with the aqueous layer and the polar head groups, while their hydrophobic regions are solvated by the lipid tails . The Riniker group, also using molecular dynamics, reported that the formation of a contiguous hydrophobic surface patch was important for the passive membrane permeation of certain cyclic decapeptides . Our work shows that this principle is also important for the permeability of nonpeptidic macrocycles and indeed that, at least for the compounds in our set, the degree of spatial bias between polar and nonpolar regions of the molecule in the most stable low dielectric conformation is a major determinant of passive permeability.…”

“…It is a well-established hypothesis that the membrane permeability of macrocycles can be enhanced for MCs that can undergo a so-called “chameleonic” conformational changethat is when, in a low dielectric environment, the molecule can adopt an alternative conformation that buries polar features. ,,− The results described above establish that many of the MCs in our set can access multiple conformations in solution and that consideration of certain physicochemical properties that depend on the conformation is necessary to accurately model permeability. We therefore evaluated the extent to which chameleonic conformational change might contribute to permeability among our compounds.…”

“…Compared to acyclic compounds of comparable size, MCs have unique structural and conformational properties, and some physicochemical properties potentially relevant to passive membrane permeability can only be fully considered in the context of the specific 3D conformations a given MC can adopt. ,,,,,, For example, the extent of hydrophilic surface exposed to solvent can depend on the 3D conformation because, in certain conformations, polar atoms may be buried in the compound’s interior or be otherwise shielded from solvent. It is also thought that the flexibility of a compound may itself play a role in membrane permeability by allowing the compound to “chameleonically” alter its physicochemical properties through a conformational change as it moves between aqueous and lipid environments. ,,− …”

“…Analyses of oral MC drugs suggested that a minimum topological polar surface area (TPSA) of ∼0.2 Å 2 per dalton of MW is required to maintain aqueous solubility for compounds of this type. ,, Consequently, compounds with a MW of > 700 Da typically cannot have sufficient polar content for good solubility without exceeding the TPSA threshold of 140 Å 2 that Veber established as an approximate upper limit for good oral bioavailability. It is therefore thought that the oral bioavailability achieved by certain high-MW macrocycles and other bRo5 compounds depends, in part, on the ability of these compounds to undergo a “chameleonic” conformational change that buries or internally complements polar functionality to facilitate entry into the lipid bilayer; ,,− Cyclosporin A being the most frequently cited example of this phenomenon. − …”

“…Systematic investigation of cyclic peptide macrocycles, from the laboratories of Loke y , Fairlie, Riniker, and others, − ,− have substantially advanced our understanding of MC permeability. For example, a study of analogues of the cyclic heptapeptide sanguinamide A showed that introducing β-branched side chains, in an attempt to sterically shield amide NH groups, had minimal impact on permeability, whereas a combination of amide N -methylation and inclusion of large aliphatic side chains was often beneficial .…”