Prebiotically Plausible Autocatalytic Peptide Amyloids

Abstract

The prebiotic emergence of molecules capable both of self-replication and of storing information was a defining event at the dawn of life. Still, no plausible prebiotic self-replication of biologically relevant molecules has been demonstrated. Building upon the known templating nature of amyloids, we present two systems in which the products of a peptide-bond-forming reaction act as self-replicators to enhance the yield and stereoselectivity of their formation. This first report of an amino acid condensation that can undergo autocatalysis further supports the potential role of amyloids in prebiotic molecular evolution as an environment-responsive and information-coding system capable of self-replication.

Keywords: aggregation; amyloids; autocatalysis; origin of life; self-replication.

Figure 1

Autocatalysis with the (FR)₄ peptide amyloid. A) A schematic depicting the mechanism of amyloid‐templated autocatalytic condensation of activated amino acids. The black F and the mirror‐image red F represent the amino acid enantiomers in the reaction. B) The evolution of the product dr during the reaction of 200 μM activated dl‐Phe with 100 μM R(FR)₃ at pH 6.5 (—) and 7.1 (<L_>) at four different NaCl concentrations. C) Kinetics of product formation at 1 M NaCl, pH 6.5 for (FR)₄ (orange) and its diastereomer fR(FR)₃ (blue; independent measurement from B). The upper plot shows the concentration of the diastereomeric products as a function of time with fits to an autocatalytic reaction mechanism (—) and second‐order reaction mechanism (<L_>). The lower plot shows the derivative of the autocatalytic fits in the upper plot, depicting the reaction rate as a function of time. D) Kinetics of (FR)₄‐seeded condensation reactions with 200 μM dl‐Phe and 100 μM R(FR)₃ in 1 M NaCl at pH 6.5. The yield of the d product fR(FR)₃ is plotted in shades of blue, and the l‐product (FR)₄ yield, after subtraction of the seed concentration, is plotted in orange for the no‐seed control, pink for 5 μM (FR)₄ and red for 20 μM (FR)₄. E) Reversed‐phase HPLC chromatogram showing the condensation products of four racemic amino acids (100 μM each of Asp, Arg, Val, and Phe) with 100 μM R(FR)₃ at pH 6.5. The black trace is for no NaCl, and the red trace is at 3 M NaCl with the peaks labeled by the single‐letter code with lower‐case letters for the d‐configured residues. The elution time of each product was identified in individual reactions with each enantiomer of each amino acid.

Figure 2

Autocatalysis with the V(OV)₄ peptide amyloid. A) A schematic depicting the five reactive amines in the (OV)₄ substrate peptide. B) The evolution of the N‐terminal l‐Val (orange) and d‐Val (blue) condensation product yields upon sequential addition (circles) or single bolus addition (crosses) of activated dl‐Val. Samples were collected and stabilized in 6 M guanidine ⋅ HCl 12 h after addition of activated dl‐Val. C) Evolution of the N‐terminal specificity colored as in B and of the dr of the N‐terminal addition products (gray). The N‐terminal specificity is the amount of N‐terminal product as a percent of all single condensation products. D) The effect of NaCl and preincubation on V(OV)₄‐seeded reactions. The plot shows the change in the concentration of V(OV)₄ in reactions seeded with V(OV)₄ as well as the final concentration of the d enantiomer condensation product v(OV)₄.