The protein-only infectious agents known as prions exist within cellular matrices as populations of assembled polypeptide phases ranging from particles to amyloid fibres. These phases appear to undergo Darwinian-like selection and propagation, yet remarkably little is known about their accessible chemical and biological functions. Here we construct simple peptides that assemble into well-defined amyloid phases and define paracrystalline surfaces able to catalyse specific enantioselective chemical reactions. Structural adjustments of individual amino acid residues predictably control both the assembled crystalline order and their accessible catalytic repertoire. Notably, the density and proximity of the extended arrays of enantioselective catalytic sites achieve template-directed polymerization of new polymers. These diverse amyloid templates can now be extended as dynamic self-propagating templates for the construction of even more complex functional materials.
In living systems, dissipative processes are driven by the endergonic hydrolysis of chemical fuels such as nucleoside triphosphates. Now, through a simple model system, a transient self‐assembled state is realized by utilizing the catalytic effect of histidine on the formation and breaking of ester bonds. First, histidine facilitates the ester bond formation, which then rapidly co‐assembles to form a self‐supporting gel. An out‐of‐equilibrium state is realized owing to the cooperative catalysis by the proximal histidines in the assembled state, driving the second pathway and resulting in disassembly to sol. Cooperative effects that use the dual role of imidazoles as nucleophile and as proton donor is utilized to achieve transient assemblies. This simple system mimics the structural journey seen in microtubule formation where the substrate GTP facilitates the non‐covalent assembly and triggers a cooperative catalytic process, leading to substrate hydrolysis and subsequent disassembly.
The binding pockets of extant enzymes feature precise positioning of amino acid residues that facilitate multiple complex transformations exploiting covalent and non-covalent interactions. Reversible covalent anchoring is extensively used as an efficient tool by Nature for activating modern enzymes such as esterases and dehydratases and also for proteins like opsins for the complex process of visual phototransduction. Here we construct paracrystalline amyloid surfaces through the self-propagation of short peptides which offer binding pockets exposed with arrays of imidazoles and lysines. As covalent catalysis is utilized by modern-day enzymes, these homogeneous amyloid nanotubes exploit Schiff imine formation via the exposed lysines to efficiently hydrolyze both activated and inactivated esters. Controls where lysines were mutated with charged residues accessed similar morphologies but did not augment the rate. The designed amyloid microphases thus foreshadow the generation of binding pockets of advanced proteins and have the potential to contribute to the development of functional materials.
Biocatalytic reaction networks integrate complex cascade transformations via spatial localization of multiple enzymes confined within the cellular milieu. Inspired by natures ingenuity, we demonstrate that short peptide-based cross-b amyloid nanotubular hybrids can promote different kinds of cascade reactions, from simple two-step, to multistep, to complex convergent cascades. The compartmentalizing ability of paracrystalline cross-b phases was utilized to colocalize sarcosine oxidase (SOX) and hemin as an artificial peroxidase. Further, the catalytic potential of the amyloid nanotubes with ordered arrays of imidazoles were used as hydrolase mimic. The SOX-hemin amyloid nanohybrids featuring a single extant enzyme could integrate different logic networks to access complex digital designs with the help of three concatenated AND gates and biologically relevant stimuli as inputs.
Hydrophobic collapse plays crucial roles in protein functions, from accessing the complex three‐dimensional structures of native enzymes to the dynamic polymerization of non‐equilibrium microtubules. However, hydrophobic collapse can also lead to the thermodynamically downhill aggregation of aberrant proteins, which has interestingly led to the development of a unique class of soft nanomaterials. There remain critical gaps in the understanding of the mechanisms of how hydrophobic collapse can regulate such aggregation. Demonstrated herein is a methodology for non‐equilibrium amyloid polymerization through mutations of the core sequence of Aβ peptides by a thermodynamically activated moiety. An out of equilibrium state is realized because of the negative feedback from the transiently formed cross‐β amyloid networks. Such non‐equilibrium amyloid nanostructures were utilized to access temporal control over its electronic properties.
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. This system shows morphology‐dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen‐bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.
Living cells contain a range of densely phosphorylated surfaces, including phospholipid membranes, ribonucleoproteins, and nucleic acid polymers. Hyperphosphorylated surfaces also accumulate in neurodegenerative diseases as neurofibrillar tangles. We have synthesized and structurally characterized a precisely patterned phosphotyrosine surface and establish this assembly as a surrogate of the neuronal tangles by demonstrating its high-affinity binding to histone H1. This association with nucleic acid binding proteins underscores the role such hyperphosphorylated surfaces may play in disease and opens functional exploration into protein-phosphorylated surface interactions in a wide range of other complex assemblies.
Herein, we report the catalytic potential of short peptide based cross-β amyloid nanotubes with surface exposed histidine capable of binding hemin and showing facile cascade reactions, playing the dual roles of hydrolases and peroxidases, two of the most important classes of enzymes in extant biology.
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