Molecular Imprinting: The missing piece in the puzzle of abiogenesis? (1807.07065v1)

Abstract: In a neglected 2005 paper, Nobel Laureate Paul Lauterbur proposed that molecular imprinting in amorphous materials -- a phenomenon with an extensive experimental literature -- played a key role in abiogenesis. The present paper builds on Lauterbur's idea to propose imprint-mediated templating (IMT), a mechanism for prebiotic peptide replication that could potentially avoid a range of difficulties arising in classic gene-first and metabolism-first models of abiogenesis. Unlike models that propose prebiotic RNA synthesis, activation, and polymerization based on unknown chemistries, peptide/IMT models are compatible with demonstrably realistic prebiotic chemistries: synthesis of dilute mixtures of racemic amino acids from atmospheric gases, and polymerization of unactivated amino acids on hot, intermittently-wetted surfaces. Starting from a peptide/IMT-based genetics, plausible processes could support the elaboration of genetic and metabolic complexity in an early-Earth environment, both explaining the emergence of homochirality and providing a potential bridge to nucleic acid metabolism. Peptide/IMT models suggest directions for both theoretical and experimental inquiry.

• The paper introduces imprint-mediated templating (IMT) as a novel mechanism for peptide replication under realistic prebiotic conditions.
• It demonstrates how molecular imprinting can selectively bind simple amino acids and catalyze peptide ligation without pre-existing enzyme machinery.
• The study outlines experimental and computational strategies to validate IMT as a solution to challenges in traditional gene-first and metabolism-first abiogenesis models.

The paper "Molecular Imprinting: The missing piece in the puzzle of abiogenesis?" (1807.07065) by K. Eric Drexler builds upon a proposal by Paul Lauterbur, suggesting that molecular imprinting in amorphous materials could have played a key role in abiogenesis, specifically by mediating the replication of prebiotic peptide sequences. This mechanism, termed Imprint-Mediated Templating (IMT), is proposed as a potential solution to long-standing difficulties in classic "gene-first" (e.g., RNA world) and "metabolism-first" models of the origin of life.

The core problem in abiogenesis is the chicken-and-egg dilemma: complex genetic systems require complex metabolic machinery to synthesize and replicate their components, while complex metabolism requires a genetic system to encode the necessary enzymes and structures. Existing "gene-first" models, particularly those centered on an RNA world, face significant challenges in explaining the prebiotic synthesis and polymerization of complex nucleic acid monomers under realistic early-Earth conditions. "Metabolism-first" models, while compatible with simpler prebiotic chemistry, struggle to explain how functional complexity could accumulate and evolve without a genetic system.

The paper proposes that peptide/IMT could provide a genetic mechanism compatible with demonstrably realistic prebiotic chemistries. Unlike nucleic acids, amino acids are readily produced in simulated prebiotic environments and found in meteorites. Peptide polymerization has also been shown to occur on hot, intermittently wetted mineral surfaces via dehydrothermal cycling.

Molecular Imprinting and IMT Primer:

Molecular imprinting is a process where a labile medium reorganizes around a "template" molecule, then consolidates (e.g., by cross-linking), leaving a cavity complementary to the template. These "imprints" can selectively bind molecules of the same kind with high specificity, similar to antibodies. Imprinting occurs under general conditions with diverse media (polymers, silica, etc.) and can operate on small molecules and polymers. Crucially, imprints can also act as catalysts, for example, by stabilizing transition states or by orienting reactants. The paper focuses on product-directed catalysis, where an imprint templated by a reaction product catalyzes the formation of that same product.

IMT is proposed as a templating mechanism distinct from the Polymer-Mediated Templating (PMT) of nucleic acids. In PMT (like DNA replication), a polymer templates a complementary polymer, which then templates a copy of the original. This requires specific, pre-existing complementary monomers and polymerases. In peptide IMT, a peptide polymer templates a complementary imprint in an amorphous medium. This imprint then selectively binds and juxtaposes amino acids or peptide fragments, facilitating their ligation to form a copy of the original peptide.

Key Differences and Advantages of Peptide/IMT:

1. Monomer Requirements: PMT requires a small set of complex, physically distinctive, pairwise-complementary monomers (like the 4 DNA bases). IMT utilizes antibody-like binding in imprints, which can select simple, diverse monomers from high-entropy mixtures based on shape and chemical features, not pre-encoded complementarity.
2. Catalysis: PMT typically requires pre-existing polymerases for both template copying and complementary strand synthesis. In IMT, imprint formation (Stage 1) requires no catalysis, and the imprint itself acts as a catalyst for ligation/chain extension (Stage 2).
3. Chirality: Modern life uses homochiral polymers. Prebiotic conditions produce racemic mixtures. IMT naturally handles racemic precursors: chiral molecules create chiral imprints in racemic media, which can selectively operate on molecules of matching chirality from a racemic pool. This avoids the problem of explaining prebiotic homochirality.
4. Compatibility with Prebiotic Chemistry: Peptide/IMT aligns well with the documented prebiotic synthesis of diverse, racemic amino acids and their polymerization via dehydrothermal cycles on mineral surfaces. Prebiotic processes also yield amorphous polymers that could serve as imprinting media.

Mechanism of Peptide Replication via IMT:

The proposed mechanism involves:

• A peptide molecule interacts with a labile, amorphous medium on a surface during a wet phase.
• The medium consolidates (e.g., via heating/drying during a wet-dry cycle), forming an imprint complementary to the peptide.
• During a subsequent wet phase, the imprint selectively binds amino acids or smaller peptide fragments that match parts of the original peptide sequence.
• As the surface dries, the concentrated, juxtaposed reactants undergo product-directed ligation, forming new peptide bonds and extending or joining chains within the imprint cavity.
• Upon rewetting, the new peptide products are released, potentially to serve as templates themselves.

Wet-dry cycling is crucial. Drying concentrates reactants and drives the dehydration reactions that form peptide bonds. It also forces binding to imprints, potentially overcoming weak interactions. Wetting facilitates product release. This cycle helps manage the binding vs. turnover trade-off problematic for steady-state catalysts. Experimental evidence suggests imprints can distinguish peptides differing by a single amino acid, indicating sufficient specificity for information transfer.

Fidelity and Evolutionary Capacity:

For IMT to support Darwinian evolution, replication must be sufficiently faithful. Fidelity depends on:

• Monomer Discriminability: Differences in monomer structure, including side chains, backbone variations (alpha vs. beta amino acids), and chirality (L vs. D), increase binding affinity differences to imprints. Prebiotic mixtures contain diverse structures expected to have high discriminability.
• Chemical Environment: Differential retention of molecules by imprints during wet-dry cycles could effectively "purify" local reactant pools, enhancing fidelity.
• Sequential Steps: Like kinetic proofreading, sequential binding and reaction steps, combined with selective exclusion of flawed intermediates/products, could amplify fidelity.

System-level evolutionary capacity requires focusing sequences in sequence space under selection pressure. Selection acts on the peptide's "direct phenotype" (its structure affecting imprint formation and catalysis) and potentially its "indirect phenotype" (effects on the local environment). Surface anchoring of peptides and the immobility of imprints naturally provide localization, crucial for linking genotype to indirect phenotype.

Paths to Complex Metabolism and Cellularity:

The paper argues that peptide/IMT can naturally evolve towards greater complexity:

• Non-linear Structures: Unlike polymerases, IMT doesn't inherently favor linear, monomer-by-monomer synthesis. Branched and cyclic peptides can be directly templated and ligated, offering rich functional possibilities (e.g., improved folding, catalytic sites).
• Convergent Assembly: IMT could facilitate convergent synthesis, where longer peptides are built by ligating shorter fragments, potentially improving efficiency and fidelity ($\log_2 N$ cycles for length N).
• Ligation of Longer Sequences: Imprints of short peptide segments could bind and ligate longer polymers, enabling the generation of complex, longer sequences encoding information beyond the imprinting template's length (analogous to recombination).
• Localization and Confinement: Surface anchoring localizes polymers. Surface topography (pores, crevices) combined with wet-dry cycles can create confined aqueous compartments, analogous to membranes for localizing diffusible metabolites without requiring membrane synthesis. This provides a mechanism for local metabolic effects to influence local replication.
• Emergence of Homochirality: Localization of metabolites allows metabolic pathways to specialize around monomers of a specific chirality (e.g., L-amino acids), providing a natural explanation for the emergence of biological homochirality through spontaneous symmetry breaking.
• Enzyme-like Functionality: Templated peptides embedded within imprints could modify imprint structure, enhancing catalytic activity, moving towards enzyme-like function. Independently folded, surface-anchored or solution-phase peptides/polymers could evolve full enzymatic roles.
• Activation Chemistry: Dehydration-induced mechanical deformation of protein-like structures during wet-dry cycles could potentially be harnessed to produce chemically activated species (like amino acid esters) for solution-phase metabolism, bridging the gap to enzyme-driven chemistry.
• Incremental Membrane Evolution: Membrane-dependent function could start with semipermeable caps on pores, gradually evolving towards full membranes using peptide-based or other plausible components.

Experimental and Computational Investigation:

The paper outlines research directions:

• Experimental: Test key proof-of-principle steps like imprint-mediated peptide dimerization, chain extension, and ligation under both optimized and prebiotic-realistic conditions (wet-dry cycles, racemic mixtures, diverse monomers, mineral surfaces, relevant salts). Measure copying fidelity.
• Computational: Model molecular interactions (e.g., molecular dynamics) to understand binding specificity and catalyst design. Model system-level dynamics (e.g., Agent-Based Modeling and Simulation) to explore how complex networks of binding, ligation, transport, and imprint formation/destruction could lead to peptide replication and evolutionary capacity under heterogeneous, cyclic conditions, potentially using heuristic search methods.

Conclusion in Scientific Context:

The peptide/IMT model offers potential solutions to the core impasses in abiogenesis research. It suggests a plausible route for a genetic system to emerge from simple prebiotic chemistry without requiring the difficult synthesis of complex nucleic acids or the prior evolution of complex metabolism and cellular compartments. It provides a potential framework for understanding the incremental evolution of complex functional molecules, localized metabolism, and eventually, membrane-bound systems. While critical mechanisms require experimental validation and system-level dynamics need computational exploration, the peptide/IMT framework presents an attractive alternative hypothesis for the emergence of life.