Emergence of Complex Catalytic Functions in Minimal Peptide Systems

Mahato, Chiranjit (2026) Emergence of Complex Catalytic Functions in Minimal Peptide Systems. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Chiranjit Mahato (20RS115)) 20RS115.pdf - Submitted Version Restricted to Repository staff only Download (12MB)

Abstract

The present thesis, “Emergence of Complex Catalytic Functions in Minimal Peptide Systems”, explores the use of short peptide-based amyloid for various chemical transformations to mimic enzymatic reactions under equilibrium and non-equilibrium conditions. The catalytic amyloids have been judiciously explored to mimic several enzymatic phenomena, from promiscuous activity, cascade activity, to feedforward regulation. Further, it presents a short peptide-based amyloid for asymmetric catalysis under both equilibrium and non-equilibrium conditions. In this context, Chapter 1 briefly introduces short peptide-based amyloids, their importance as a primitive catalytic fold, and the current literature on the development of catalytic assemblies that mimic various enzymatic reactions under equilibrium and out-of-equilibrium conditions. Chapter 2 presents the exposure of dual residues on the surface of the assembly through anti-parallel packing for the cleavage of a nucleic acid congener and shows phosphoesterase activity. Solvent-exposed guanidium and imidazole residues on the cross-β microphases act synergistically to bind and process a kinetically unfavorable bond cleavage reaction. In addition, this assembly was shown to foreshadow the mutualistic biopolymer relationships that likely contributed to the chemical emergence of life. Chapter 3 demonstrates different pathways for introducing metal ions into short-peptide-based assemblies to explore different catalytic regimes. Exposure of imidazole and tyrosine residues was utilized to capture Cu(II) and improve oxidase activity, RNase activity, and hydrolase-oxidase cascade activity. Further, pathway dependency on catalytic activity was also explored in various catalytic activities. Chapter 4 presents the importance of the chiral hydrophobic surface of short peptide-based amyloid for asymmetric sulfoxidation. The binding capability of peptide assembly was utilized to bind hemin and mimic the peroxidase enzyme active site. Further, promiscuous activity was used to design a feedforward-driven reaction network to facilitate sulfoxidation, suggesting a plausible role in facilitating protometabolic networks on the early Earth. Chapter 5 features the development of substrate-driven short-peptide-based assemblies for the stereoselective olefin cyclopropanation reaction. The development of non-equilibrium assembly was explored by utilizing surface-exposed imidazole residues to cleave in situ generated cyclopropane ester product via hydrolase activity. Chapter 6 provides an overview of the work and summarizes the significant findings of these studies. In addition, a broad overview of the possible future directions has been discussed.

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