Here we show that 4-aminocyclohexanecarboxylic acid is a rigid stretcher building block for the preparation of cyclic peptides that self-assemble to form peptide nanotubes with large diameter and hydrophobic pores.

Cyclic peptides with disc-shaped structures have emerged as potent building blocks for the preparation of new biomaterialsi nf ields ranging from biological to material science. In this work, we analyze in depth the self-assembling properties of an ew type of cyclic peptidesb ased on the alternation of a-residues and cyclic d-amino acids (a,d-CPs). To examine the preferred stacking properties adopted by cyclic peptides bearing this type of amino acids, we carried out as ynergistic in vitro/in silico approximation by using simple dimeric models and then extended to nanotubes. Althought hesen ew cyclic peptides( a,d-CPs) can interact either in ap arallelo ra ntiparallel fashion, our results confirm that although the parallel b-sheet is more stable, it can be switched to the antiparallel stacking by choosing residues that can establish favorable cross-strand interactions. Moreover, the subsequent comparison by using the same methodology but applied to a,g-CPs models, up to the moment assumeda sa ntiparallel-like d,l-a-CPs, led to unforeseen conclusions that put into question preliminaryc onjecturesa bout these systems. Surprisingly,t hey tend to adopt ap arallel b-sheet directed by the skeleton interactions. These results imply ac hange of paradigm with respect to cyclic peptided esigns that shouldb ec onsidered for dimers and nanotubes.Scheme1.Peptide nanotube models formed by stacking of cyclicpeptides: a) d,l-a-CP andc )b-CP (bottom) in af lat conformation and b) structure of someC Ps containing g-Acas (a,g-CP,3a,g-CP,and g-CP,f rom left to right) that canalso form nanotubes. Models of antiparallel, for d,l-a-CPs, or parallel, for d,l-a-CPs and for b-CPs, type b-sheet structures are also illustrated.Scheme2.Structure of the d-Ach and model of b-sheeti nteractions (parallel at the top or antiparallel at the bottom) of d,l-peptide strands upon intercalation of a d-Ach after each amino acid of identical chirality ( d,left) or after each residue (d,l-a,d-CP,right). Carbonyland NH groups are denotedin blue and red, respectively, depending on their relative orientation in the disc-shaped conformation;for a-residuesred color was assigned to d-residues whereas blue color was attributed to l-residues, respectively.Alternatively, d-Achs have the carbonyl and NH groups always with different colors, one in red pointing in the same direction as the d-residuesa nd the othero ne in blue as the l-amino acids.Scheme6.Model of nanotube SCPN9 obtained by the assembling CP9 and,o nt he right, the computer-generated model in whicha ll the amino acidss ide chains were changed to methyl groups. At the bottom,t op-view model of the threedifferent dimeric forms for each type of interactions (parallela nd antiparallel) to evaluate the side chaincross-strand interactions between two consecutive cyclic peptides. Only in the antiparallel form Ccan two salt-bridged interactionsb ee stablished betweenG lu and Lysside chains.His-Argpairs are also observed in other stacking models (E, A, or F) but in these cases, the alignment of Arg residues t...

Cell membranes define the boundaries of life and primarily consist of phospholipids. Living organisms assemble phospholipids by enzymatically coupling two hydrophobic tails to a soluble polar head group. Previous studies have taken advantage of micellar assembly to couple single-chain precursors, forming non-canonical phospholipids. However, biomimetic nonenzymatic coupling of two alkyl tails to a polar head-group remains challenging, likely due to the sluggish reaction kinetics of the initial coupling step. Here we demonstrate rapid de novo formation of biomimetic liposomes in water using dual oxime bond formation between two alkyl chains and a phosphocholine head group. Membranes can be generated from non-amphiphilic, water-soluble precursors at physiological conditions using micromolar concentrations of precursors. We demonstrate that functional membrane proteins can be reconstituted into synthetic oxime liposomes from bacterial extracts in the absence of detergent-like molecules.