The transition from inanimate materials to the earliest forms of life must have involved multiplication of a catalytically active polymer that is able to replicate. The semiconservative replication that is characteristic of genetic information transfer requires strands that contain more than one type of nucleobase. Short strands of RNA can act as catalysts, but attempts to induce efficient self-copying of mixed sequences (containing four different nucleobases) have been unsuccessful with ribonucleotides. Here we show that inhibition by spent monomers, formed by the hydrolysis of the activated nucleotides, is the cause for incomplete extension of growing daughter strands on RNA templates. Immobilization of strands and periodic displacement of the solution containing the activated monomers overcome this inhibition. Any of the four nucleobases (A/C/G/U) is successfully copied in the absence of enzymes. We conclude therefore that in a prebiotic world, oligoribonucleotides may have formed and undergone self-copying on surfaces.
How the biochemical machinery evolved from simple precursors is an open question. Here we show that ribonucleotides and amino acids condense to peptidyl RNAs in the absence of enzymes under conditions established for genetic copying. Untemplated formation of RNA strands that can encode genetic information, formation of peptidyl chains linked to RNA, and formation of the cofactors NAD+, FAD, and ATP all occur under the same conditions. In the peptidyl RNAs, the peptide chains are phosphoramidate-linked to a ribonucleotide. Peptidyl RNAs with long peptide chains were selected from an initial pool when a lipophilic phase simulating the interior of membranes was offered, and free peptides were released upon acidification. Our results show that key molecules of genetics, catalysis, and metabolism can emerge under the same conditions, without a mineral surface, without an enzyme, and without the need for chemical pre-activation.
Template-directed incorporation of nucleotides at the terminus of a growing complementary strand is the basis of replication. For RNA, this process can occur in the absence of enzymes, if the ribonucleotides are first converted to an active species with a leaving group. Thus far, the activation required a separate chemical step, complicating prebiotically plausible scenarios. Here we show that a combination of a carbodiimide and an organocatalyst induces near-quantitative incorporation of any of the four ribonucleotides. Upon in situ activation, adenosine monophosphate was found to also form oligomers in aqueous solution. So, both de novo strand formation and sequence-specific copying can occur without an artificial synthetic step.
Der templatgesteuerte Einbau von Nukleotiden am Terminus eines Komplementärstrangs ist die Grundlage der Replikation. Im Fall von RNA kann dieser Vorgang in Abwesenheit von Enzymen stattfinden, wenn die Ribonukleotide vorher in eine Aktivspezies mit einer Abgangsgruppe überführt werden. Bisher war für diese Aktivierung ein separater chemischer Schritt nötig, was komplizierte präbiotisch plausible Szenarios erfordert. Wir zeigen nun, dass die Kombination eines Carbodiimids und eines Organokatalysators den annähernd quantitativen Einbau jedes der vier Ribonukleotide induziert. Bei In‐situ‐Aktivierung von Adenosinmonophosphat bilden sich gleichzeitig Oligomere in wässriger Lösung. Es können also Strangbildung und sequenzspezifische Kopiervorgänge ohne künstlichen Syntheseschritt stattfinden.
Wie sich die heutige biochemische Maschinerie aus einfachen Vorläufern entwickelte, ist eine ungelöste Frage. Wir zeigen nun, dass Ribonukleotide und Aminosäuren in Abwesenheit von Enzymen zu Peptidyl‐RNAs kondensieren, und zwar unter Bedingungen, die auch spontanes genetisches Kopieren induzieren. Es treten templatfreie Bildung von RNA‐Strängen, die genetische Information codieren können, die Bildung von Peptidyl‐RNAs und die Bildung der Cofaktoren NAD+, FAD und ATP unter den gleichen Bedingungen auf. In den Peptidyl‐RNAs sind die Peptidketten über eine Phosphorsäureamidgruppe an ein Ribonukleotid gebunden. Peptidyl‐RNAs mit langen Peptidketten lassen sich aus einem Pool selektieren, wenn eine lipophile Phase angeboten wird, die das Innere von Membranen simuliert. Freie Peptide lassen sich aus Peptidyl‐RNA durch Ansäuern freisetzen. Unsere Ergebnisse zeigen, dass Schlüsselmoleküle der Genetik, der Katalyse und des Metabolismus unter denselben Bedingungen entstehen können, ohne dass es mineralische Oberflächen, Enzyme oder eine chemische Voraktivierung bräuchte.
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