A topologically complex peptide [4]catenane with the crossing number of 12 was synthesized by a folding and assembly strategy wherein the folding and metal-directed self-assembly of a short peptide fragment occur simultaneously. The latent Ω-looped conformation of the Pro-Gly-Pro sequence was found only when pyridines at the C- and N-termini coordinatively bind metal ions (Ag(I) or Au(I) ). Crystallographic studies revealed that the Ω-looped motifs formed four M3 L3 macrocycles that were intermolecularly entwined to generate an unprecedented peptide [4]catenane topology.

At opologically complex peptide [4]catenane with the crossing number of 12 was synthesized by af olding and assembly strategy wherein the folding and metal-directed selfassembly of as hort peptide fragment occur simultaneously. The latent W-looped conformation of the Pro-Gly-Pro sequence was found only when pyridines at the C-and Ntermini coordinatively bind metal ions (Ag I or Au I ). Crystallographic studies revealed that the W-looped motifs formed four M 3 L 3 macrocycles that were intermolecularly entwined to generate an unprecedented peptide [4]catenane topology. Scheme 1. Schematic representation of the self-assembly of [Ag 12 (2) 12 ] 12+ (3)with atopology of a1 2-crossing [4]catenane.

The de novo construction of repeat proteins has received much attention from biologists and chemists, yet that of a β-barrel structure, one of the most well-known classes, has not been accomplished to date. Here, we report the first chemical construction of a β-barrel tertiary structure with a pore through a combination of peptide folding and metal-directed self-assembly. Coordination of zinc salts to an eight-residue peptide fragment bearing β-strand- and loop-forming sequences resulted in a β-barrel in which six-stranded cylindrical antiparallel β-sheets formed a hydrophobic pore with a specific shape.

In this work, a peptide [2]catenane was created by exploiting the strong tendency of the Pro-Gly-Pro (PGP) sequence to fold into an ³-loop. Ditopic heptapeptide ligand 1, which includes the PGP sequence, formed peptide [2]catenane 2 on complexation with Ag + . Moreover, addition/removal of Na + triggered a reversible structural change between 2 and twisted macrocycle 3. Keywords: Interlocking molecules | Peptide folding | Structural switchPeptide loops are inconspicuous but important structural elements of proteins and can induce strand entanglement, as often seen in protein knots and catenanes.1 Such entanglements are believed to enhance the mechanical stability of proteins. Unlike the artificial design of α-helix/β-sheet mimics, 2 that of peptide-loop conformations remains difficult because of the absence of intra-strand hydrogen bonds in the loop, and it is therefore largely unexplored. Recently, we reported that the short Pro-Gly-Pro (PGP) peptide sequence is folded into an "³"-shaped loop on concerted metal-coordination, and this gives rise to a highly entangled 12-crossing [4]catenane.3 In this selfassembly, the latent ³-folding propensity of the PGP sequence is expressed by inter-strand interactions during the entanglement of the two loop motifs. To generalize this observation and demonstrate the potential of the folding-and-assembly strategy for creating highly complex discrete structures, we designed new ditopic heptapeptide ligand 1, in which PGP and GPP tripeptide sequences are linked through a rigid imino(1,3-phenylene)carbonyl spacer (Scheme 1). We show that, through Ag + -triggered folding and assembly, ligand 1, which has a longer and more flexible peptide sequence than the ligand used in our previous study, was folded into an expanded ³-loop and assembled in concert into peptide [2]catenane 2 ([(Ag¢1) 2 ] 2+ ). This catenane structure appears to be stabilized by various inter-strand interactions between the two peptide macrocycles (hydrogen bonding, ππ, Agπ). Upon addition of Na + , the inter-strand hydrogen bonding was disrupted by the Na + £O=C coordination and 2 unexpectedly underwent a drastic structural change into a [Ag 2 (1) 2 Na] 3+ macrocycle. Thus, a flexible loop can also serve as a building block for dynamic peptide-based assemblies.Pyridine-tethered heptapeptide 1 was synthesized by solution-phase peptide synthesis (see the Supporting Information (SI)). Complexation of 1 with Ag + was first carried out using a crystallization strategy. Triple layers of peptide ligand 1 (5¯mol) in CHCl 3 (0.15 mL), a buffer solution (0.15 mL, CHCl 3 /EtOH = 1:1 (v/v)), and silver(I) bis(trifluoromethylsulfonyl)imide (AgNTf 2 , 5¯mol) in EtOH (0.15 mL) were prepared in a capped microtube and slowly diffused into each other at 10°C. After a few days, single block-shaped crystals of excellent quality were obtained. A crystallographic study revealed the formation of [2]catenane 2, in which the two [Ag¢1]+ macrocycles are interlocked in C 2 symmetry (Figure 1a). The interlocked structure is induced by mult...

Concerted folding and assembly processes are necessary for protein self-assembly, yet such a concerted strategy has rarely been attempted by synthetic chemists. In this work, we have created a new porous peptide structure through a coordination-driven folding-and-assembly strategy. A porous framework with 1.5 nm-sized pores and a P helical peptide scaffold was successfully obtained by complexation of AgNTf and tripeptide ligands containing the Gly-Pro-Pro sequence. The pores were modified in various ways with retention of the latent P helical conformation of the peptide ligand.