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-Gly2 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.