Towards Prebiotic Catalytic Amyloids Using High Throughput Screening

Abstract

Enzymes are capable of directing complex stereospecific transformations and of accelerating reaction rates many orders of magnitude. As even the simplest known enzymes comprise thousands of atoms, the question arises as to how such exquisite catalysts evolved. A logical predecessor would be shorter peptides, but they lack the defined structure and size that are apparently necessary for enzyme functions. However, some very short peptides are able to assemble into amyloids, thereby forming a well-defined tertiary structure called the cross-β-sheet, which bestows unique properties upon the peptides. We have hypothesized that amyloids could have been the catalytically active precursor to modern enzymes. To test this hypothesis, we designed an amyloid peptide library that could be screened for catalytic activity. Our approach, amenable to high-throughput methodologies, allowed us to find several peptides and peptide mixtures that form amyloids with esterase activity. These results indicate that amyloids, with their stability in a wide range of conditions and their potential as catalysts with low sequence specificity, would indeed be fitting precursors to modern enzymes. Furthermore, our approach can be efficiently expanded upon in library size, screening conditions, and target activity to yield novel amyloid catalysts with potential applications in aqueous-organic mixtures, at high temperature and in other extreme conditions that could be advantageous for industrial applications.

Zinc-binding structure of a catalytic amyloid from solid-state NMR

“…A classical example is carbonic anhydrase, where a zinc ion is coordinated by three histidines from two β-strands and a hydroxide ion to catalyze the hydration of carbon dioxide to form bicarbonate (2). It has been hypothesized that such enzyme structure and function might have evolved from short peptides that self-assemble into repeat structures (3)(4)(5)(6)(7), in which the metal ions played a significant role by stabilizing the amyloid structure as well as catalyzing reactions. Cu 2+ and Zn 2+ ions also bind amyloid proteins involved in neurodegenerative disorders at physiological concentrations of these ions (8)(9)(10)(11)(12)(13)(14).…”

Short Self‐Assembling Peptides Are Able to Bind to Copper and Activate Oxygen

“…[13] Herein, we show that the self-assembly of short de novo designed peptides results in the formation of efficient supramolecular catalysts that are capable of oxygen activation. Moreover,wes how that supramolecular assemblies are capable of supporting oxygenation catalysis that does not rely on radicals.T his finding underscores the fact that amyloidlike assemblies formed by even very short peptides can facilitate various chemical transformations in ah ighly sequence-specific manner.C onsidering recent findings that amyloid-supported metal sequestration and catalysis is more likely to be the rule than an exception, [3,14] we expect de novo designed self-assembled catalytic peptides to combine the highly controlled metal coordination sphere common in homogeneous catalysis with the practical advantages of heterogeneous catalysts.M oreover,s ynergistic interactions observed in these systems provide additional opportunities for high-throughput screening for catalytic function. Finally, the diversity of reactions catalyzed by simple peptide assemblies lends further support to the amyloid-first hypothesis of the emergence of enzymatic function.…”

Visible‐Light Microscopic Discovery of Up to 150 μm Long Helical Amyloid Fibrils Built of the Dodecapeptide H‐(Val‐Ala‐Leu)4‐OH and of Decapeptides Derived from Insulin

“… See also catalytically active amyloids and enantioselective self‐aggregation of peptides to form nanofibers . …”