No abstract

Cavity creation is a key to the origin of biological functions. Small cavities such as enzyme pockets are created simply through liner peptide folding. Nature can create much larger cavities by threading and entangling large peptide rings, as learned from gigantic virus capsids, where not only chemical structures but the topology of threaded rings must be controlled. Although interlocked molecules are a topic of current interest, they have for decades been explored merely as elements of molecular machines, or as a synthetic challenge. No research has specifically targeted them for, and succesfully achieved, cavity creation. Here we report the emergence of a huge capsular framework via multiple threading of metal–peptide rings. Six equivalent C4-propeller-shaped rings, each consisting of four oligopeptides and Ag+, are threaded by each other a total of twelve times (crossing number: 24) to assemble into a well-defined 4 nm-sized sphere, which acts as a huge molecular capsule.

Despite the frequent occurrence of knotted frameworks in protein structures, the latent potential of peptide strands to form entangled structures is rarely discussed in peptide chemistry. Here we report the construction of highly entangled molecular topologies from Ag(I) ions and tripeptide ligands. The efficient entanglement of metal−peptide strands and the wide scope for design of the amino acid side chains in these ligands enabled the construction of metal−peptide 9 1 torus knots and 10 1 2 torus links. Moreover, steric control of the peptide side chain induced ring opening and twisting of the torus framework, which resulted in an infinite toroidal supercoil nanostructure.

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...