Semi‐Rationally Designed Short Peptides Self‐Assemble and Bind Hemin to Promote Cyclopropanation

Abstract

The self‐assembly of short peptides gives rise to versatile nanoassemblies capable of promoting efficient catalysis. We have semi‐rationally designed a series of seven‐residue peptides that form hemin‐binding catalytic amyloids to facilitate enantioselective cyclopropanation with efficiencies that rival those of engineered hemin proteins. These results demonstrate that: 1) Catalytic amyloids can bind complex metallocofactors to promote practically important multisubstrate transformations. 2) Even essentially flat surfaces of amyloid assemblies can impart a substantial degree of enantioselectivity without the need for extensive optimization. 3) The ease of peptide preparation allows for straightforward incorporation of unnatural amino acids and the preparation of peptides made from d‐amino acids with complete reversal of enantioselectivity.

Multivalent display of chemical signals on self‐assembled peptide scaffolds

“…Ac-K 4 (ChaKChaE) 2 -NH 2 Lysine residues 3C [153] Ac-K 2 (ChaKChaE) 2 -NH 2 Lysine residues 3C [153] Ac-E 4 (ChaKChaE) 2 -NH 2 Glutamic acid residues 3C [153] Ac-E(CH 2 CHO)EEEAAAVVVK(C 16 )-NH 2 Silver nanoparticles 3C [154] Fmoc-FFECG Silver nanoparticles 3C [155] C 16 -V 3 A 3 K 4 -NH 2 Folate 3D [156] CKKAAVVK-C 12 KLVWLPK-NH2 3D [157] FFERGD 10-hydroxycamptothecin (HCPT)/cisplatin 3D [158] (VPGVG) 80 (VPGSG) 60 EgA1 3D [159] Nap-G D F D F Phosphate/YSV 3D [160] PhAc-FFAG LDD 3D [16] LVFFGFLG RGD/camptothecin 3D [161] Ac-IHIHIQI-NH 2 Histidine residues 3E [162][163][164] Ac-IHIHIYI-NH 2 Histidine residues 3E [163] Im-KLVFFAL-NH 2 Lysine residues/imidazole groups 3E [165] Ac-KLVFFAL-NH 2 Lysine residues 3E [166] Sialic acid 3F [167,168] AQZ/near-infrared quantum dots/Alexa Fluor 633 3F [169] Ac-HLVFFAL-NH 2 Histidine residues/hemin 3E [170] VK2H (HSG(VK) 4 V D PPT(KV) 4 -NH 2 ) Histidine residues 3E [171] Phenylalanine Zn 2+ 3E [172] 1,4,5,8-naphthalenetetracarboxylic acid diimide Proline residues 3E [173] PFE-C 12 Proline residues 3E [174] PEF-C 12 Proline residues 3E [174] PAEPKI-C 16 Proline residues 3E [175] C 10 -FFVK Lysine residues/Fmoc-Tyrosine 3E [176] Ac-LHLHLQL-NH 2 Histidine residues/hemin 3E [177] Ac-LHLHLFL-NH 2 Histidine residues/hemin 3E [177] Ac-LILHLFL-NH 2 Histidine residues/hemin 3E [177] HN-D PL-CONH-C 16 D-proline/leucine residues/IrCp* 3E [178] KKAAVV(K)-C 12 RTL (RTLAFVRFK) 3F [179] SFEEA...…”

“…Korendovych and coworkers screened their existing library of β-sheet-forming amphipathic heptamers for hemin coordination and found that nanofibers of the sequence Ac-LHLHLQL-NH 2 successfully bound hemin. [177] They replaced the Gln residue with Phe to increase the…”

Self‐Assembling Catalytic Peptide Nanomaterials Capable of Highly Efficient Peroxidase Activity

“…Allp eptides formed self-assembled structures in the presence of hemin in a1:10 co-factor:peptide ratio to ensure full co-factor binding. [4] Remarkably,n early all peptide-hemin assemblies promoted oxidation, in some cases with high efficiency when compared to hemin alone (Figure S1, Supporting Information and Table 1). Interestingly,a ssemblies formed by LMLHLFL-hemin had the highest peroxidase activity,yet this catalystgave only moderate yields in carbene transfer.…”

“…[3] Recently,w eh ave demonstrated that assemblies formed by de novo designed peptides bind heme to promote cyclopropanation efficiently and in an enantioselective manner. [4] This reaction requires productivea ssociation of the catalyst with multiple substrates and catalytic turnover withoutt he loss of heme in af lat and fairly featureless system.H ere, we set out to explore the potentialo fh eme-peptide assemblies forp romoting peroxidase-type activity.N atural peroxidases that utilize high valent iron species represent av ery commonc lass of enzymes capable of extremely versatile reactivity,i ncluding polymerization,h ydroxylation and N, and O-dealkylations, among many others. [5] In addition to the practical utility of peroxidases, ranging from waste water purification to polymer productionand biotechnology,peroxidase activity has been extensively studied, providing many benchmarks in both enzymatic and model systems.…”

“…Interestingly,a ssemblies formed by LMLHLFL-hemin had the highest peroxidase activity,yet this catalystgave only moderate yields in carbene transfer. [4] While the limiteds et of peptides studied precluded us from establishing detailed structure-activity relationships we noted that hydrophobic b-branched amino acids (Ile, Val) as well as amyloidogenic (Gln) residues in position 2p ro-Scheme1.Substratesusedtotestfor peroxidase activity of hemin-binding peptideassemblies.…”