Interconversion Rates between Conformational States as Rationale for the Membrane Permeability of Cyclosporines

Abstract

Cyclic peptides have regained interest as potential inhibitors of challenging targets but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone, it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA. The structure of CsE differs only in a backbone methylation, but its membrane permeability is one order of magnitude lower. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA.

Conformational Flexibility Is a Determinant of Permeability for Cyclosporin

“…The inter-conversion rates between conformations that favor and disfavor membrane permeability are thought to drive permeability, particularly when the time scales of conversion are slower than permeation. 39 On average, insertion of cyclosporin A into a lipid membrane is an endothermic process, governed by an enthalpic penalty that is counterbalanced by favorable entropic changes. 52 The enthalpic contribution to insertion might be brought about by: (i) a reordering of water molecules about the peptide surface; (ii) changes in hydrogen bonding between water and cyclosporin A; or, (iii) a combination of both processes.…”

Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability

“…Markov state models (MSMs) [47][48][49][50] are a powerful tool to analyze the conformational dynamics in MD simulations. Here, we generated core-set Markov models of PF1022A (1) in chloroform using common nearest neighbor (CNN) based clustering 49,[51][52][53] and the PyEMMA package. 54 This procedure has been used successfully with other cyclic peptides.…”

Toward the Elucidation of the Mechanism for Passive Membrane Permeability of Cyclic Peptides

“…More challenging and potentially more informative are therefore 'permeability cliffs', that is, structurally very similar molecules with large differences in permeability. Such cases [19,20] show that the ability to adopt a closed conformation in an apolar environment is a necessary but not sufficient condition for permeability. For example, side chains can heavily influence the population of the closed conformation in water, which was found to correlate with permeability for a series of closely related peptides [20].…”

“…Most studies on the permeability of large cyclic peptides have been based on compounds with known closed conformation (from crystal structures and/or NMR solution structures). Computational approaches to predict the permeability of new compounds, whether simple (e.g., minimum 3D PSA [18]) or more sophisticated (such as in [5,19,20]), require the knowledge of the closed conformation. However, identifying such conformations for cyclic peptides 'beyond hexamers' using in silico conformer generators becomes very difficult due to the large number of degrees of freedom (although already reduced through cyclization).…”