Enantioselective Ketone Reduction by Catalytic Amyloids

Sarma, Khyati (2025) Enantioselective Ketone Reduction by Catalytic Amyloids. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Khyati Sarma (23 MP016)) 23MP016_Thesis_file.pdf - Submitted Version Download (2MB)

Abstract

Through million years of evolutionary journey, extant enzymes are conferred with highly conserved three-dimensional folds that are capable of showing remarkably specific chemical transformations with great efficiency. Further, contemporary enzymes can effectively bind and activate co-enzymes/co-factors to carry out various catalytic reaction stereo-specifically. However, there remains a critical gap in understanding how early enzymatic folds, despite lacking the precisely folded binding pockets like modern enzymes, could catalyze stereoselective chemical transformations that are crucial for the emergence of homochirality during the chemical origins of life. In this context, short peptide-based self-assemblies have often been argued as early protein folds due to their capabilities to self-assemble into extended periodic nanostructures and demonstrate diverse catalytic roles. In my thesis work, we envisage to develop highly cationic short peptide-based assemblies that can effectively recruit small negatively charged co-factors as hydride transfer agents to facilitate early oxidoreductive processes, thereby fueling the emergence of early protometabolism. We have developed catalytic peptide nanostructures that can capitalize its surface-exposed binding sites punctuated with kinetically locked cationic residues (quaternized amines). Moreover, the chiral surfaces of the nanostructures provide various interactions with hydrophobic substrates that can also effectively bind the co-enzyme, sodium borohydride leveraging the enantioselective reduction of prochiral ketones. This work underscores the enantioselective catalytic power of short peptides foreshadowing their possible roles in the emergence of homochiral chemical inventory in prebiotic earth.

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