The past, present and future of protein-based materials.

Protein-based materials are finding new uses and applications after millennia of impacting the daily life of humans. Some of the earliest uses of protein-based materials are still evident in silk and wool textiles and leather goods. Today, even as silks, wools and leathers are still be used in traditional ways, these proteins are now seen as promising materials for biomaterials, vehicles of drug delivery and components of high-tech fabrics. With the advent of biosynthetic methods and streamlined means of protein purification, protein-based materials-recombinant and otherwise-are being used in a host of applications at the cutting edge of medicine, electronics, materials science and even fashion. This commentary aims to discuss a handful of these applications while taking a critical look at where protein-based materials may be used in the future.

Glycal Metallanitrenes for 2-Amino Sugar Synthesis: Amidoglycosylation of Gulal-, Allal-, Glucal-, and Galactal 3-Carbamates.

The rhodium(II)-catalyzed oxidative cyclization of glycal 3-carbamates with in situ incorporation of an alcohol nucleophile at the anomeric position provides access to a range of 2-amino sugars having 1,2-trans-2,3-cis stereochemistry, a structural motif present in compounds of medicinal and biological significance such as the streptothricin group of antibiotics and the Chitinase inhibitor allosamidin. All of the diastereomeric d-glycal 3-carbamates have been investigated, revealing significant differences in anomeric stereoselectivity depending on substrate stereochemistry and protecting groups. In addition, some substrates were prone to forming C3-oxidized dihydropyranone byproducts under the reaction conditions. Allal- and gulal 3-carbamates provided uniformly high stereo- and chemoselectivity, while for glucal substrates, acyclic, electron-withdrawing protecting groups at the 4 O and 6 O positions were required. Galactal 3-carbamates have been the most challenging substrates; formation of their amidoglycosylation products is most effective with an electron-withdrawing 6 O-Ts substituent and a sterically demanding 4 O-TBS group. These results suggest a mechanism whereby conformational and electronic factors determine the partitioning of an intermediate acyl nitrenoid between alkene addition, leading to amidoglycosylation, and C3-H insertion, providing the dihydropyranone byproduct. Along the amidoglycosylation pathway, high anomeric selectivity results when a glycosyl aziridine intermediate is favored over an aziridine-opened oxocarbenium donor.

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination.

It is widely accepted that structural rigidity is required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply to highly selective catalytic peptides that often exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging to study both experimentally and computationally. Herein, we utilize molecular dynamics simulations to investigate the role of conformational mobility on the reactivity and selectivity exhibited by a catalytic, ß-turn-biased peptide in an atroposelective bromination reaction. By means of cluster analysis, multiple distinct conformers of the peptide and a catalyst-substrate complex were identified in the simulations, all of which were corroborated by experimental NMR measurements. The simulations also revealed that a shift in the conformational equilibrium of the peptidic catalyst occurs upon addition of substrate, and the degree of change varies among different substrates. On the basis of these data, we propose a correlation between the composition of the peptide conformational ensemble and its catalytic properties. Moreover, these findings highlight the importance of conformational dynamics in catalytic, asymmetric reactions mediated by oligopeptides, unveiled through high-level, state-of-the-art computational modeling.

Diversity of Secondary Structure in Catalytic Peptides with ß-Turn-Biased Sequences.

X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical ß-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H-1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.

Aspartyl Oxidation Catalysts That Dial In Functional Group Selectivity, along with Regio- and Stereoselectivity.

A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions. The analogous portability of a small-molecule catalyst for truly orthogonal chemical reactivity is rare. Herein, we report aspartic acid containing peptides that can be directed to different sectors of a substrate for which the danger of cross-reactivity looms large. A transiently formed aspartyl peracid catalyst can participate either as an electrophilic oxidant to catalyze alkene epoxidation or as a nucleophilic oxidant to mediate the Baeyer-Villiger oxidation (BVO) of ketones. We show in this study that an appended peptide sequence can dictate the mode of reactivity for this conserved catalytic functional group within a substrate that has the potential to undergo both alkene epoxidation and BVO; in both cases the additional aspects of chemical selectivity (regio- and stereoselectivity) are high. This sequence-dependent tuning of a common catalytic moiety for functional group selective reactions constitutes a biomimetic strategy that may impact late-stage diversification of complex polyfunctional molecules.

Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer-Villiger Oxidation.

The structural analysis of a peptide-based catalyst for the Baeyer-Villiger oxidation (BVO) is reported. This unique structure is then analyzed in the context of its previously documented facility to control selectivity (both enantioselectivity and migratory aptitude) in catalytic reactions. The effects of additives on the solution conformation of the peptide are found to be dramatic, revealing substrate-specific interactions and a possible "induced fit" model. The experimental observation of dynamic behavior supports the notion that flexibility in stereoselective catalysts can be an advantageous feature.

Function-Oriented Investigations of a Peptide-Based Catalyst that Mediates Enantioselective Allylic Alcohol Epoxidation.

We detail an investigation of a peptide-based catalyst 6 that is effective for the site- (>100:1:1) and enantioselective epoxidation (86% ee) of farnesol. Studies of the substrate scope exhibited by the catalyst are included, along with an exploration of optimized reaction conditions. Mechanistic studies are reported, including relative rate determinations for the catalyst and propionic acid, a historical perspective, truncation studies, and modeling using NMR data. Our compiled data advances our understanding of the inner workings of a catalyst that was identified through combinatorial means.

Dihydropyranone formation by ipso C-H activation in a glucal 3-carbamate-derived rhodium acyl nitrenoid.

By using (N-tosyloxy)-3-O-carbamoyl-D-glucal 10, which removes the need for a hypervalent iodine(III) oxidant, we provide evidence for rhodium nitrenoid-mediated ipso C-H activation as the origin of a C3-oxidized dihydropyranone product 3. This system may be especially susceptible to such a pathway because of the ease of forming a cation upon hydride transfer to the rhodium-complexed acyl nitrene.