Racemic beta-sheets as templates of relevance to the origin of homochirality of peptides: lessons from crystal chemistry.

The origin of life is a historical event that has left no relevant fossils; therefore, it is unrealistic to reconstruct the chronology of its occurrence. Instead, by performing laboratory experiments under conditions that resemble the prebiotic world, one might validate feasible reaction pathways and reconstruct model systems of artificial life. Creating such life in a test tube should go a long way toward removing the shroud of mystery over how it began naturally. The riddle of the appearance of natural proteins and nucleic acids--that is, biopolymers wholly consisting of homochiral subunits (L-amino acids and D-sugars, respectively)--from the unanimated racemic prebiotic world is still unsolved. There are two hypotheses concerning the sequence of their emergence: one maintains that long homochiral (isotactic) peptides must have been formed after the appearance of the first living systems, whereas the other presumes that such biopolymers preceded the primeval enzymes. The latter scenario necessitates, however, the operation of nonlinear synthetic routes, because the polymerization of racemates in ideal solutions yields chains composed of residues of either handedness. In this Account, we suggest applying lessons learned from crystal chemistry, in which molecules from isotropic media are converted into crystals with three-dimensional (3D) periodic order, to understand how the generation of homochiral peptides from racemic alpha-amino acids might be achieved, despite its seemingly overwhelming complexity. We describe systems that include the self-assembly of activated alpha-amino acids either in two-dimensional (2D) or in 3D crystals, followed by a partial lattice-controlled polymerization at the crystal-aqueous solution interface. We also discuss the polymerization of mixtures of activated hydrophobic racemic alpha-amino acids in aqueous solutions, as initiated by primary amines or thiols. The distribution of the diastereomeric oligopeptides was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MS/MS with monomers enantioselectively tagged with deuterium. The reaction performed in aqueous solutions encompasses the following sequential steps: (i) formation of a library of short racemic peptides enriched with isotactic diastereoisomers during the early stages of the polymerization, and (ii) self-assembly of oligopeptides into racemic beta-sheet colloidal-like aggregates that are delineated by enantiotopic sites or rims; these operate as templates (nuclei) for regio-enantioselective growth in the ensuing steps of chain elongation. Desymmetrization of the racemic mixtures of peptides was achieved with enantiopure alpha-amino acid esters as initiators. The enantiomeric excess of the isotactic peptides, not including the initiator, varies with chain length, the result of a cross-enantiomeric impeding mechanism. Our results suggest a feasible scenario in which primitive homochiral peptides might have emerged early in the prebiotic world.