Abstract
Engineered biocircuits designed with biological components have the capacity to expand and augment living functions. Here we demonstrate that proteases can be integrated into digital or analog biocircuits to process biological information. We first construct peptide-caged liposomes that treat protease activity as two-valued (i.e., signal is 0 or 1) operations to construct the biological equivalent of Boolean logic gates, comparators and analog-to-digital converters. We use these modules to assemble a cell-free biocircuit that can combine with bacteria-containing blood, quantify bacteria burden, and then calculate and unlock a selective drug dose. By contrast, we treat protease activity as multi-valued (i.e., signal is between 0 and 1) by controlling the degree to which a pool of enzymes is shared between two target substrates. We perform operations on these analog values by manipulating substrate concentrations and combine these operations to solve the mathematical problem Learning Parity with Noise (LPN). These results show that protease activity can be used to process biological information by binary Boolean logic, or as multi-valued analog signals under conditions where substrate resources are shared.
Highlights
Engineered biocircuits designed with biological components have the capacity to expand and augment living functions
To design an analogto-digital converter (ADC) biocircuit using protease activity as the core signal, we constructed biological analogs of comparators by using liposomes locked by an outer peptide cage[50,51] (Fig. 2a and Fig. S2a, b)
With increasing peptide crosslinking densities, these biocomparators (b0 – bi) served to reference the level of input protease activity (GzmB) required to fully degrade the peptide cage (IEFDSGK, Table S1) and expose the lipid core (Fig. S2c), analogous to the reference voltages stored in electronic comparators
Summary
Engineered biocircuits designed with biological components have the capacity to expand and augment living functions. We first construct peptide-caged liposomes that treat protease activity as two-valued (i.e., signal is 0 or 1) operations to construct the biological equivalent of Boolean logic gates, comparators and analog-to-digital converters. We perform operations on these analog values by manipulating substrate concentrations and combine these operations to solve the mathematical problem Learning Parity with Noise (LPN) These results show that protease activity can be used to process biological information by binary Boolean logic, or as multi-valued analog signals under conditions where substrate resources are shared. The flow of biological information can be controlled by directing how resources are partitioned[44] This control strategy is fundamental to the design of biological systems that implement analog operations such as stochastic biocircuits[45], autonomous diagnostics[12], and synthetic ribosomes that insulate genetic circuits[46]
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