[reaction: see text] The technique of native chemical ligation enables the total chemical synthesis of proteins. This method is limited, however, by an absolute requirement for a cysteine residue at the ligation juncture. Here, this restriction is overcome with a new chemical ligation method in which a phosphinobenzenethiol is used to link a thioester and azide. The product is an amide with no residual atoms.

Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.

Phenylalanine (Phe)-derived molecules have been exploited as low molecular weight hydrogelators. Perturbing the hydrophobic and p-p interactions that promote self-assembly and hydrogelation of these derivatives will facilitate improved understanding of hydrogelation phenomena and the design of small molecule hydrogelators with novel properties. The efficient self-assembly and hydrogelation of Fmoc-protected pentafluorophenylalanine (Fmoc-F 5 -Phe) are reported herein. Suspensions of Fmoc-F 5 -Phe in water undergo rapid self-assembly to entangled fibrillar structures within minutes, giving rise to rigid supramolecular gels. Self-assembly occurs at concentrations as low as 2 mM (0.1 wt%). Variation of the fluorinated aromatic side chain or N-terminal functionalization perturbs hydrogelation, implicating fluorous and p-p interactions as the primary determinants for molecular recognition and self-assembly. The hydrophobic and electronic properties of F 5 -Phe provide remarkable potential for functional self-assembly in a minimal amino acid scaffold.

L-Selenocysteine (Sec or U) has been called the "21st amino acid". 1 Like the twenty common amino acids, selenocysteine is inserted during the translation of mRNA and has its own tRNA Sec and codon, UGA. This codon also serves as the opal stop codon. Decoding a UGA codon as one for selenocysteine requires a special structure in the 3′ untranslated region of the mRNA called a selenocysteine insertion sequence (SECIS) element. Because eukaryotic and prokaryotic cells use a different SECIS element to decode UGA as selenocysteine, the production of eukaryotic selenocysteine-containing proteins in prokaryotes is problematic. 2 Here, we describe a general semisynthetic route to proteins containing selenocysteine. 3,4 In "native chemical ligation", the thiolate of an N-terminal cysteine residue in one peptide attacks a C-terminal thioester in another peptide to produce, ultimately, an amide bond between the two peptides (Scheme 1). 5 "Expressed protein ligation" is an extension in which the C-terminal thioester is produced by using recombinant DNA (rDNA) technology. 6 We reasoned that selenocysteine, like cysteine, could effect both native chemical ligation and expressed protein ligation, and thereby provide a means to incorporate selenocysteine into proteins.We used AcGlySCH 2 C(O)NHCH 3 as a model thioester to test the feasibility of using selenocysteine in native chemical ligation. 7 Reaction with cystine ((CysOH) 2 ) in the presence of the reducing agent tris-(2-carboxyethyl)phosphine (TCEP) produced AcGlyCysOH, as well as some (AcGlyCysOH) 2 . When selenocystine ((SecOH) 2 ) was used in the same reaction, the product was (AcGlySecOH) 2 . 8 A selenolate (RSe -) is more nucleophilic than is its analogous thiolate (RS -). 9 Moreover, the pK a of a selenol (RSeH) is lower than that of its analogous thiol (RSH). 9a,10 These properties suggested to us that native chemical ligation with selenocysteine could be more rapid than with cysteine, especially at low pH. To test this hypothesis, we used the chromogenic thioester AcGly-SC 6 H 4 -p-NO 2 (1; Scheme 2) to determine the rate of native chemical ligation as a function of pH. 11 The resulting pH-rate profile is shown in Figure 1. Reaction with selenocysteine is 10 3 -fold faster than with cysteine at pH 5.0. Thus, native chemical ligation with selenocysteine can be chemoselective. 12 Having demonstrated the effectiveness of selenocysteine in native chemical ligation, we next set out to explore its utility in expressed protein ligation. As a model protein, we chose ribonuclease A (RNase A; EC 3.1.27.5; Figure 2), which has been the object of much seminal work in protein chemistry. 14 RNase A has 8 cysteine residues that form 4 disulfide bonds in the native For other means to incorporate selenocysteine into semisynthetic and synthetic proteins, see: (a) Wu, Z. P.; Hilvert, D. J. Am. Chem. Soc. 1989, 111, 4513-4514. (b) Fiori, S.; Pegoraro, S.; Rudolph-Bohner, S.; Cramer, J.; Moroder, L. Biopolymers 2000, 53, 550-564. (4) For a means to produce selenopeptide libraries o...