Postdoctoral Scholar, University of California, San Diego
Autocatalytic self-assembling peptides shed light on life’s chemical origins
Central role of self-replication
One of the essential features of life is self-reproduction, which occurs both on the molecular scale through the replication of genetic polymers (DNA, RNA), as well as larger scales through the reproduction of cells. While modern living organisms are extremely complex molecular assemblies that are the product of billions of years of evolution, there has been significant interest in developing simpler self-replicating systems.
Autocatalytic chemical reactions, whereby a molecule is able to catalyze its own formation, mimic nature’s ability to generate identical copies of relevant biomolecules. In particular, autocatalytic self-assembling peptides could be used as efficient building blocks for the construction of bioinspired nanomaterials, as well as for the study of the underlying mechanisms of self-association and principles that led to the first living systems on Earth.
Linking autocatalysis and self-assembly
My research is focused on the development of non-enzymatic and chemoselective methodologies capable of autocatalytically producing triskelion peptides that self-associate into spherical nanostructures. Serial transfer experiments demonstrate that autocatalysis successfully leads to continual self-assembly of three-dimensional nanospheres. Triskelion-based spherical architectures offer an opportunity to organize biomolecules and chemical reactions in unique, nanoscale compartments. Moreover, the ease with which the size and properties of autocatalytic peptide nanospheres can be controlled allows their use in fields such as biosensing, medicine and electronics. Peptide-based autocatalysts that are capable of self-assembly also represent a powerful tool for the construction of self-synthesizing biomaterials and may shed light on understanding life’s chemical origins and early evolution.
Abstract: Cell membranes are dynamic structures found in all living organisms. There have been numerous constructs that model phospholipid membranes. However, unlike natural membranes, these biomimetic systems cannot sustain growth owing to an inability to replenish phospholipid-synthesizing catalysts. Here we report on the design and synthesis of artificial membranes embedded with synthetic, self-reproducing catalysts capable of perpetuating phospholipid bilayer formation. Replacing the complex biochemical pathways used in nature with an autocatalyst that also drives lipid synthesis leads to the continual formation of triazole phospholipids and membrane-bound oligotriazole catalysts from simpler starting materials. In addition to continual phospholipid synthesis and vesicle growth, the synthetic membranes are capable of remodeling their physical composition in response to changes in the environment by preferentially incorporating specific precursors. These results demonstrate that complex membranes capable of indefinite self-synthesis can emerge when supplied with simpler chemical building blocks.
Pub.: 24 Jun '15, Pinned: 18 Oct '17
Abstract: The origin of homochirality in living systems is often attributed to the generation of enantiomeric differences in a pool of chiral prebiotic molecules, but none of the possible physiochemical processes considered can produce the significant imbalance required if homochiral biopolymers are to result from simple coupling of suitable precursor molecules. This implies a central role either for additional processes that can selectively amplify an initially minute enantiomeric difference in the starting material, or for a nonenzymatic process by which biopolymers undergo chiroselective molecular replication. Given that molecular self-replication and the capacity for selection are necessary conditions for the emergence of life, chiroselective replication of biopolymers seems a particularly attractive process for explaining homochirality in nature. Here we report that a 32-residue peptide replicator, designed according to our earlier principles, is capable of efficiently amplifying homochiral products from a racemic mixture of peptide fragments through a chiroselective autocatalytic cycle. The chiroselective amplification process discriminates between structures possessing even single stereochemical mutations within otherwise homochiral sequences. Moreover, the system exhibits a dynamic stereochemical 'editing' function; in contrast to the previously observed error correction, it makes use of heterochiral sequences that arise through uncatalysed background reactions to catalyse the production of the homochiral product. These results support the idea that self-replicating polypeptides could have played a key role in the origin of homochirality on Earth.
Pub.: 10 Mar '01, Pinned: 18 Oct '17
Abstract: The production of amino acids and their condensation to polypeptides under plausibly prebiotic conditions have long been known. But despite the central importance of molecular self-replication in the origin of life, the feasibility of peptide self-replication has not been established experimentally. Here we report an example of a self-replicating peptide. We show that a 32-residue alpha-helical peptide based on the leucine-zipper domain of the yeast transcription factor GCN4 can act autocatalytically in templating its own synthesis by accelerating the thioester-promoted amide-bond condensation of 15- and 17-residue fragments in neutral, dilute aqueous solutions. The self-replication process displays parabolic growth pattern with the initial rates of product formation correlating with the square-foot of initial template concentration.
Pub.: 08 Aug '96, Pinned: 18 Oct '17
Abstract: Self-replicating molecules are likely to have played an important role in the origin of life, and a small number of fully synthetic self-replicators have already been described. Yet it remains an open question which factors most effectively bias the replication toward the far-from-equilibrium distributions characterizing even simple organisms. We report here two self-replicating peptide-derived macrocycles that emerge from a small dynamic combinatorial library and compete for a common feedstock. Replication is driven by nanostructure formation, resulting from the assembly of the peptides into fibers held together by beta sheets. Which of the two replicators becomes dominant is influenced by whether the sample is shaken or stirred. These results establish that mechanical forces can act as a selection pressure in the competition between replicators and can determine the outcome of a covalent synthesis.
Pub.: 20 Mar '10, Pinned: 18 Oct '17
Abstract: To design the next generation of so-called "smart" materials, researchers will need to develop chemical systems that respond, adapt, and multitask. Because many of these features occur in living systems, we expect that such advanced artificial systems will be inspired by nature. In particular, these new materials should ultimately combine three key properties of life: metabolism, mutation, and self-replication. In this Account, we discuss our endeavors toward the design of such advanced functional materials. First, we focus on dynamic molecular libraries. These molecular and supramolecular chemical systems are based on mixtures of reversibly interacting molecules that are coupled within networks of thermodynamic equilibria. We will explain how the superimposition of combinatorial networks at different length scales of structural organization can provide valuable hierarchical dynamics for producing complex functional systems. In particular, our experimental results highlight why these libraries are of interest for the design of responsive materials and how their functional properties can be modulated by various chemical and physical stimuli. Then, we introduce examples in which these dynamic combinatorial systems can be coupled to kinetic feedback loops to produce self-replicating pathways that amplify a selected component from the equilibrated libraries. Finally, we discuss the discovery of highly functional self-replicating supramolecular assemblies that can transfer an electric signal in space and time. We show how these wires can be directly incorporated within an electronic nanocircuit by self-organization and functional feedback loops. Because the network topologies act as complex algorithms to process information, we present these systems in this order to provide context for their potential for extending the current generation of responsive materials. We propose a general description for a potential autonomous (self-constructing) material. Such a system should self-assemble among several possible molecular combinations in response to external information (input) and possibly self-replicate to amplify its structure. Ultimately, its functional response (output) can drive the self-assembly of the system and also serve a mechanism to transfer this initial information. Far from equilibrium, such synergistic processes could give rise to evolving, "information gaining" systems which become increasingly complex because internal self-organization rapidly reduces the potential energy surrounding the system.
Pub.: 27 Apr '12, Pinned: 18 Oct '17
Abstract: Minimal self-replicating systems typically consist of three components: a product molecule, and two substrate molecules that become joined to form another product molecule. An important characteristic of self-replicating systems is the ability of the product to catalyze the formation of additional product, resulting in autocatalytic behavior. Recent advances in the area of self-replication have led to improved efficiency of autocatalysis, both by increasing the fraction of product molecules that can participate in further rounds of replication, and by improving the efficiency of the catalysts themselves. This review analyzes chemical self-replicating systems that have been developed to date and discusses ongoing challenges in this area of research.
Pub.: 24 Nov '04, Pinned: 18 Oct '17
Abstract: Thanks to their intrinsic network topologies, dynamic combinatorial libraries (DCLs) represent new tools for investigating fundamental aspects related to self-organization and adaptation processes. Very recently the first examples integrating self-replication features within DCLs have pushed even further the idea of implementing dynamic combinatorial chemistry (DCC) towards minimal systems capable of self-construction and/or evolution. Indeed, feedback loop processes - in particular in the form of autocatalytic reactions - are keystones to build dynamic supersystems which could possibly approach the roots of "Darwinian" evolvability at mesoscale. This topic of current interest also shows significant potentialities beyond its fundamental character, because truly smart and autonomous materials for the future will have to respond to changes of their environment by selecting and by exponentially amplifying their fittest constituents.
Pub.: 06 Jul '11, Pinned: 18 Oct '17
Abstract: Most self-replicating peptide systems are made of α-helix forming sequences. However, it has been postulated that shorter and simpler peptides may also serve as templates for replication when arranged into well-defined structures. We describe here the design and characterization of new peptides that form soluble β-sheet aggregates that serve to significantly accelerate their ligation and self-replication. We then discuss the relevance of these phenomena to early molecular evolution, in light of additional functionality associated with β-sheet assemblies.
Pub.: 06 Dec '11, Pinned: 18 Oct '17
Abstract: Self-replication is a fundamental concept. The idea of an entity that can repeatedly create more of itself has captured the imagination of many thinkers from von Neumann to Vonnegut. Beyond the sciences and science fiction, autocatalysis has found currency in economics and language theory, and has raised ethical fears memorably summed up by the "gray goo" trope. Autocatalysis is central to the propagation of life and intrinsic to many other biological processes. This includes the modern conception of evolution, which has radically altered humanity's image of itself. Organisms can be thought of as imperfect self-replicators which produce closely-related species, allowing for selection and evolution. Hence, any consideration of self-replication raises one of the most profound questions of all: what is life? Minimal self-replicating systems have been studied with the aim of understanding the principles underlying living systems, allowing us to refine our concepts of biological fitness and chemical stability, self-organization and emergence, and ultimately to discover how chemistry may become biology.
Pub.: 16 Oct '13, Pinned: 18 Oct '17
Abstract: Over the past 25 years, there has been a surge of development in research towards self-replication and self-replicating systems. The interest in these systems relates to one of the most fundamental questions posed in all fields of science – How did life on earth begin? Investigating how the self-replication process evolved may hold the key to understanding the emergence and evolution of living systems and, ultimately, gain a clear insight into the origin of life on earth. This introductory review aims to highlight the fundamental prerequisites of self-replication along with the important research that has been conducted over the past few decades.
Pub.: 12 Apr '16, Pinned: 18 Oct '17
Abstract: In this review we discuss systems of self-replicating molecules in the context of the origin of life and the synthesis of de novo life. One of the important aspects of life is the ability to reproduce and evolve continuously. In this review we consider some of the prerequisites for obtaining unbounded evolution of self-replicating molecules and describe some recent advances in this field. While evolution experiments involving self-replicating molecules have shown promising results, true open-ended evolution has not been realized so far. A full understanding of the requirements for open-ended evolution would provide a better understanding of how life could have emerged from molecular building blocks and what is needed to create a minimal form of life in the laboratory.
Pub.: 12 Jul '17, Pinned: 18 Oct '17
Abstract: Autocatalytic chemical reactions, whereby a molecule is able to catalyze its own formation from a set of precursors, mimic nature's ability to generate identical copies of relevant biomolecules, and are thought to have been crucial for the origin of life. While several molecular autocatalysts have been previously reported, coupling autocatalytic behavior to macromolecular self-assembly has been challenging. Here, we report a non-enzymatic and chemoselective methodology capable of autocatalytically producing triskelion peptides that self-associate into spherical bioinspired nanostructures. Serial transfer experiments demonstrate that oligotriazole autocatalysis successfully leads to continual self-assembly of three-dimensional nanospheres. Triskelion-based spherical architectures offer an opportunity to organize biomolecules and chemical reactions in unique, nanoscale compartments. The use of peptide-based autocatalysts that are capable of self-assembly represents a promising method for the development of self-synthesizing biomaterials, and may shed light on understanding life's chemical origins.Molecules that act as both autocatalysts and material precursors offer exciting prospects for self-synthesizing materials. Here, the authors design a triazole peptide that self-replicates and then self-assembles into nanostructures, coupling autocatalytic and assembly pathways to realize a reproducing supramolecular system.
Pub.: 30 Sep '17, Pinned: 18 Oct '17