Side-Chain Interactions in d/l Peptide Nanotubes: Studies by Crystallography, NMR Spectroscopy and Molecular Dynamics

Our understanding of the factors affecting the stability of cyclic d/l peptide (CP) nanotubes remains underdeveloped. In this work, we investigate the impact of side chain alignment, hydrophobicity and charge on CP nanotube stability through X-ray crystallography, NMR spectroscopy and molecular dynamics (MD) simulations. We characterise the distinct CP-CP alignments that can form and identify stable and unstable dimers by MD simulation. We measure H-bond half-lives of synthesised CPs by ¹ H-D exchange experiments and find good correlation with predicted CP-CP stabilities. We find that hydrophobic amino acids improve CP dimer stability but experimentally reduce solubility. Charged amino acids either increase or decrease CP dimer stability depending on the relative orientation and composition of charged groups. X-ray crystal structures are solved for two CPs, revealing non-tubular folded conformations. Ultimately, this work will assist the educated design of stable tubular structures for potential applications in biomedicine.