Feedback driven autonomous cycles of assembly and disassembly from minimal building blocks.

The construction of complex systems by simple chemicals that can display emergent network dynamics might contribute to our understanding of complex behavior from simple organic reactions. Here we design single amino acid/dipeptide-based systems that exhibit multiple periodic changes of (dis)assembly under non-equilibrium conditions in closed system, importantly in the absence of evolved biocatalysts. The two-component based building block exploits pH driven non-covalent assembly and time-delayed accelerated catalysis from self-assembled state to install orthogonal feedback loops with a single batch of reactants.

Allosteric Control of the Catalytic Properties of Dipeptide-Based Supramolecular Assemblies.

Allostery, as seen in extant biology, governs the activity regulation of enzymes through the redistribution of conformational equilibria upon binding an effector. Herein, a minimal design is demonstrated where a dipeptide can exploit dynamic imine linkage to condense with simple aldehydes to access spherical aggregates as catalytically active states, which facilitates an orthogonal reaction due to the closer proximity of catalytic residues (imidazoles). The allosteric site (amine) of the minimal catalyst can concomitantly bind to an inhibitor via a dynamic exchange, which leads to the alternation of the energy landscape of the self-assembled state, resulting in downregulation of catalytic activity.

Emergence of Photomodulated Protometabolism by Short Peptide-Based Assemblies.

In the early Earth, rudimentary enzymes must have utilized the available light energy source to modulate protometabolic processes. Herein, we report the light-responsive C-C bond manipulation via short peptide-based assemblies bound to the photosensitive molecular cofactor (azo-based photoswitch) where the energy of the light source regulated the binding sites which subsequently modulated the retro-aldolase activity. In the presence of a continual source of high-energy photons, temporal realization of a catalytically more proficient state could be achieved under nonequilibrium conditions.

Covalent Organic Framework Cladding on Peptide-Amphiphile-Based Biomimetic Catalysts.

Peptide-based biomimetic catalysts are promising materials for efficient catalytic activity in various biochemical transformations. However, their lack of operational stability and fragile nature in non-aqueous media limit their practical applications. In this study, we have developed a cladding technique to stabilize biomimetic catalysts within porous covalent organic framework (COF) scaffolds.

Nonequilibrium Amyloid Polymers Exploit Dynamic Covalent Linkage to Temporally Control Charge-Selective Catalysis.

Extant proteins exploit thermodynamically activated negatively charged coenzymes and hydrotropes to temporally access mechanistically important conformations that regulate vital biological functions, from metabolic reactions to expression modulation. Herein, we show that a short amyloid peptide can bind to a small molecular coenzyme by exploiting reversible covalent linkage to polymerize and access catalytically proficient nonequilibrium amyloid microphases. Subsequent hydrolysis of the activated coenzyme leads to depolymerization, realizing a variance of the surface charge of the assembly as a function of time.

Systems chemistry of peptide-assemblies for biochemical transformations.

During the billions of years of the evolutionary journey, primitive polymers, involved in proto metabolic pathways with low catalytic activity, played critical roles in the emergence of modern enzymes with remarkable substrate specificity. The precise positioning of amino acid residues and the complex orchestrated interplay in the binding pockets of evolved enzymes promote covalent and non-covalent interactions to foster a diverse set of complex catalytic transformations. Recent efforts to emulate the structural and functional information of extant enzymes by minimal peptide based assemblies have attempted to provide a holistic approach that could help in discerning the prebiotic origins of catalytically active binding pockets of advanced proteins.

Emergence of a Promiscuous Peroxidase Under Non-Equilibrium Conditions.

Herein, we report the substrate induced generation of a transient catalytic microenvironment from a single amino acid functionalized fatty acid in presence of a cofactor hemin. The catalytic state accessed under non-equilibrium conditions showed acceleration of peroxidase activity resulting in degradation of the substrate and subsequently led to disassembly. Equilibrated systems could not access the three-dimensional microphases and showed substantially lower catalytic activity.

Aldolase Cascade Facilitated by Self-Assembled Nanotubes from Short Peptide Amphiphiles.

Early evolution benefited from a complex network of reactions involving multiple C-C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C-C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C-C bond cleavage and formation.

Condensates of short peptides and ATP for the temporal regulation of cytochrome c activity.

Herein, we report the generation of simple condensates of short peptides with ATP, which are spatiotemporally formed under dissipative conditions created in presence of ATP-ase. These coacervates could imbibe cytochrome c and temporally modulate a redox reaction catalyzed by the entrapped protein, thus mimicking the advanced functional machinery of transient intercellular membraneless condensates of large proteins and RNA.