A self-replicating peptide nucleic acid

Abstract

While the non-enzymatic ligation and template-directed synthesis of peptide nucleic acids (PNA) have been reported since 1995, a case of self-replication of PNA has not been achieved yet. Here, we present evidence for autocatalytic feedback in a template directed synthesis of a self-complementary hexa-PNA from two trimeric building blocks. The course of the reaction was monitored in the presence of increasing initial concentrations of the product by RP-HPLC. Kinetic modeling with the SimFit program revealed parabolic growth characteristics. The observed template effect, as well as the rate of ligation, was significantly influenced by nucleophilic catalysts, pH value, and uncharged co-solvents. Systematic optimization of the reaction conditions allowed us to increase the autocatalytic efficiency of the system by two orders of magnitude. Our findings contribute to the hypothesis that PNA may have served as a primordial genetic molecule and was involved in a potential precursor of a RNA world.

Versatility of peptide nucleic acids (PNAs): role in chemical biology, drug discovery, and origins of life

“…The presence of diaminobutyric acid, a building block for PNA, and its analogs in Murchison meteorite also suggests that PNA might have preceded RNA. Recent reports on PNA self‐replicating system analogous to biological replication, Keidrowski's work on short self‐complementary PNA sequence capable of promoting autocatalytic self‐replication, and Leslie E. Orgel and coworker's convincing report on the genetic transition between PNA and RNA without any loss of information strengthen the speculations on the role of PNA in origin of life (Figure ).…”

Energy Threshold for Chiral Symmetry Breaking in Molecular Self-Replication

“…41,42 It is important to note that the Soai reaction is itself a singularity, not only in its (to date) unique capacity to amplify ee but also in its stunning autocatalytic efficiency and persistence; the irreversible nature of this reaction allows it to exhibit true exponential kinetics rather than the parabolic kinetic profile characteristic of the product inhibition that ultimately suppresses template-directed self-replication in non-enzymatic nucleic acid or peptide replicators as reaction turnover increases. [43][44][45] Persistence is key to the sustained propagation and amplification of a small initial imbalance of enantiomers, a problem related to that of proposed pre-genetic metabolic cycles that must remain stable against inexorable decay from inapposite side reactions. 46,47 Starting from the threshold product ee that we determined in the Soai reaction, the gradient for chiral amplification is slow, reaching less than 5% ee even after 10 million reaction turnovers.…”

Templated Self‐Replication in Biomimetic Systems

“…The function via the nonenzymatic condensation of activated oligonucleotides on complementary templates. [51] More recently, analogous ligation-based autocatalytic replication of peptide nucleic acid was reported, [52] demonstrating that nucleic acids with a noncharged and achiral backbone are also suitable candidates for synthetic self-replicators or primordial genetic material. [49,50] Both systems used a carbodiimide as activating reagent to enable the ligation of di-or tri-nucleotides on a complementary template.…”

“…While Kiedrowski used phosphorylated tridesoxynucleotides as substrates, Zielinski and Orgel's system incorporated more efficient phosphoramidate chemistry for ligation, which was later used to generate systems roughly two orders of magnitude more efficient than their previous replicators. [51] More recently, analogous ligation-based autocatalytic replication of peptide nucleic acid was reported, [52] demonstrating that nucleic acids with a noncharged and achiral backbone are also suitable candidates for synthetic self-replicators or primordial genetic material. Notably, the systems described above are currently the only enzyme-free nucleic acid replicators capable of genuine autocatalytic self-replication.…”