Exploring the Esterase Catalytic Activity of Minimalist Heptapeptide Amyloid Fibers

This paper investigates the esterase activity of minimalist amyloid fibers composed of short seven‐residue peptides, IHIHIHI (IH7) and IHIHIQI (IH7Q), with a particular focus on the role of the sixth residue position within the peptide sequence. Through computational simulations and analyses, we explore the molecular mechanisms underlying catalysis in these amyloid‐based enzymes. Contrary to initial hypotheses, our study reveals that the twist angle of the fiber, and thus the catalytic site's environment, is not notably affected by the sixth residue. Instead, the sixth residue interacts with the p‐nitrophenylacetate (pNPA) substrate, particularly through its −NO2 group, potentially enhancing catalysis. Quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction mechanism suggest that the polarizing effect of glutamine enhances catalytic activity by forming a stabilizing network of hydrogen bonds with pNPA, leading to lower energy barriers and a more exergonic reaction. Our findings provide valuable insights into the intricate interplay between peptide sequence, structural arrangement, and catalytic function in amyloid‐based enzymes, offering potentially valuable information for the design and optimization of biomimetic catalysts. The esterase activity of minimalist amyloid fibers, made up of seven‐residue peptides IHIHIHI and IHIHIQI, is examined using computational techniques. Contrary to initial assumptions, computational simulations reveal that the twist angle of the fiber is not notably influenced by the sixth residue, the reduction in the energy barrier when Gln is present being attributed to the formation of hydrogen bonds with the substrate.