Emergence of Catalytic Triad by Short Peptide Based Nanofibrillar Assemblies

Abstract

Through millions of years of the evolutionary journey, contemporary enzymes observed in extant metabolic pathways have evolved to become specialized, in contrast to their ancestors, which displayed promiscuous activities with wider substrate specificities. However, there remain critical gaps in our understanding of how these early enzymes could show such catalytic versatility despite lacking the complex three-dimensional folds of the existing modern-day enzymes. Herein, we report the emergence of a promiscuous catalytic triad by short amyloid peptide based nanofibers that access paracrystalline folds of β-sheets to expose three residues (lysine, imidazole, and tyrosine) toward solvent. The ordered folded nanostructures could simultaneously catalyze two metabolically relevant chemical transformations via C–O and C–C bond manipulations, displaying both hydrolase and retro-aldolase-like activities. Further, the latent catalytic capabilities of the short peptide based promiscuous folds also helped in processing a cascade transformation, suggesting the important role they might have played in protometabolism and early evolutionary processes.

Computation-Driven Rational Design of Self-Assembled Short Peptides for Catalytic Hydrogen Production

“…X-ray diffraction (XRD) analysis has corroborated that IIQ naturally formed a highly organized bilayer structure, irrespective of the presence of metal cofactors. This organization aligns with a reported structural model, where the observed peaks at ∼4.6 and ∼10.8 Å correspond to the backbone spacing of the β-sheet structure within a single layer and the distance between two neighboring layers of β-sheets (Figure A). − Intriguingly, IIH does not exhibit a pronounced pattern of intersheet distance (Figure S6), hinting at a more flexible stacking arrangement. Far-ultraviolet circular dichroism spectra at ∼217 nm further validated the formation of fibril-like structures, consistent with previous reports. , These spectra also indicate that both Zn 2+ and Cu 2+ have a strong tendency in promoting the formation of such fibril-like structures (Figures B and S7).…”

Self-Assembly of Multimolecular Components for Engineering Enzyme-Mimetic Materials

“…Das and co-workers self-assembled the Im-KLVFFAL peptide, positioning lysine residues and imidazole groups to create catalytic centers mimicking retroaldolase and hydrolase. This close proximity allowed for effective cascaded hydrolysis and retroaldol reactions …”

Emergence of Photomodulated Protometabolism by Short Peptide-Based Assemblies

“…Temporal modulation of aldolase-like activity by judiciously exploiting the environmental changes and possibilities of promiscuous activities might have been advantageous for the chemical emergence of protometabolic activities (Figure b). Herein, we report that short peptide-based amyloid-like assemblies can bind photosensitive cofactors and modulate C–C bond cleavage (aldolase-like activity), one of the important chemical transformations in the context of metabolic pathways (Figure a,b) . Solvent-exposed lysines were used as catalytic units to cleave an aldol adduct ( M ) via the Schiff base formation, a strategy exploited in type I aldolases (Figure b) .…”