Molecular Insights into the Selective Ion Permeation and Confined Water Behavior in a Transmembrane d/l-α Cyclic Peptide Nanotube.

Cyclic peptide nanotubes (CPNTs) represent a class of self-assembled nanostructures with tunable chemical functionality and biomimetic channel-like behavior. In this work, we investigate the selective transport of three cations (Na+, K+, and Cs+) and one anion (Cl-) through a CPNT composed of eight stacked cyclo-[Cys-d-Gly-Met-d-Gly]2 rings embedded within a biologically realistic yeast lipid bilayer using molecular dynamics simulations. Potential of mean force (PMF) calculations reveal a strong preference for cation permeation, with Na+ and K+ overcoming moderate barriers, while Cs+ exhibits hindered translocation and transient trapping due to higher entry and exit barriers. In contrast, Cl- faces substantial deep wells in the α-planes of the CPNT, suggesting unfavorable interactions with the nanotube backbone. Electrostatic interaction analysis further shows that cations engage favorably with CPNT backbone carbonyls, whereas Cl- is electrostatically excluded. Hydration analysis shows that spatial confinement in the CPNT alters the solvation shell, with Na+ retaining more hydration and interacting with the CPNT backbone via water bridges, followed by K+ and Cs+ forming more direct interactions with backbone carbonyl groups. Water structure and dynamics inside the nanotube are also modulated by the presence of cations, disrupting the typical 1-2-1-2 arrangement and reducing axial water diffusion, most notably in the presence of Na+. Analysis of water dipole orientation reveals pronounced ion-induced ordering of channel water without the emergence of orientational defects along the hydrogen-bond network. These findings elucidate the molecular-level determinants of ion selectivity in CPNTs and provide design principles for developing peptide-based artificial channels in lipid membranes.