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Updated: May 22, 2025

Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
Published on: January 16, 2016
Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers
Miranda N Limbach1, Edward T Lindberg1, Cynthiya Shrestha1
1Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
Abstract:
Conformational flexibility allows macrocyclic peptides like cyclosporine A (CycA) to cross membranes, yet drug design leveraging this property has largely failed. A key challenge is linking specific conformers to function, as different conformers govern permeability versus target binding. We reveal a mechanism that enhances CycA and alisporivir (ALI) permeability: trans-to-cis isomerization at MeVal11-MeBmt1 creates conformers that remain "soluble" in both membrane-like and aqueous environments. A biased equilibrium favors this conformer in protic environments, while a lipophilic conformer with cis MeLeu9-MeLeu10 dominates in aprotic conditions. This mechanism explains why CycH, Valspodar (VALSPO), and O-acetyl CycA (OAc-CycA) fail to cross membranes─they adopt similar states but lack this biased equilibrium. Our findings provide a new strategy for designing membrane-permeable N-methylated macrocycles and underscore the role of high-energy conformers as transition states between membrane permeability and target engagement─offering critical insights for drug development.
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