Prebiotic Chemistry

How did the first living system originate? How many different chemical possibilities can be realized to generate a living system and what is the probability for such a system? Are there universal principles that guided the origins of life and how can we identify these principles?

These are the very fundamental questions that are experimentally addressed by the Trapp Research Group.

We are investigating kinetically and thermodynamically selected reaction pathways  to form building blocks relevant for life, i.e. amino acids, sugars, pyrimidine bases, purine bases, nucleotides and surfactants. An advanced experiment to simulate prebiotic reaction conditions in parallel reactors with continuous reaction progress analysis of complex reaction mixtures is developed to obtain information about the reaction dynamics in complex reaction networks leading to the synthesis of nucleotide oligomers and polymers, in particular of DNA and RNA nucleosides and nucleotides. By this approach catalytically active components and molecules that undergo selective interactions, stabilize or activate molecules can be identified and missing reaction pathways revealed. Cooperative effects in reaction networks are the key to increase the complexity of generated structures.  This requires sophisticated analytical techniques to meet the requirements of a high sample throughput, i.e. integration of reaction and separation in a single step and multiplexing approaches, to analyze and evaluate mixtures of high complexity. The tools required to perform these studies are developed in our laboratory. Furthermore mechanisms of self-replication of nucleotides to store information leading to living systems are studied.

Homochirality is directly connected to the occurrence of life. Therefore one focus is on the stereochemical investigations including the stereodynamics of activated molecular species to explain the selective formation of certain stereoisomers and to find an explanation for homochirality. Stereochemically relevant systems are synthesized and investigated as switchable chiral catalysts in a number of organic transformations that can explain the formation of the (homochiral) building blocks essential for the development of life.

Such switchable catalytic systems, where selectivity can be changed by external physical properties, i.e. by temperature, pH, concentration gradients to control the kinetics and thermodynamics might be a key for explaining self-amplifying systems, which finally lead to self-replication of building blocks and macromolecular structures such as RNA or DNA.

These investigations are supported by the extension of simulation tools already in use in the Trapp lab to predict and evaluate reaction parameters in such reaction networks based on kinetic and thermodynamic data.

A prebiotic route to DNA

How were the building-blocks of life first formed on the early Earth? As yet, only partially satisfactory answers to this question are available. However, one thing is clear: The process of biological evolution that has given rise to the diversity of life on our planet must have been preceded by a phase of chemical evolution. During this ‘prebiotic’ stage, the first polymeric molecules capable of storing information and reproducing themselves were randomly assembled from organic precursors that were available on the early Earth. The most efficient replicators subsequently evolved into the macromolecular informational nucleic acids – DNA and RNA – that became the basis for all forms of life on our planet.

For billions of years, DNA has been the primary carrier of hereditary information in biological organisms. DNA strands are made up of four types of chemical subunits, and the genetic information it contains is encoded in the linear sequence of these ‘nucleosides’. Moreover, the four subunits comprise two complementary pairs. Interactions between two strands with complementary sequences are responsible for the formation of the famous double helix, and play a crucial role in DNA replication. RNA also has vital functions in the replication of DNA and in the translation of nucleotide sequences into proteins.

Which of these two types of nucleic acid came first? The unanimous answer to that question up to now was RNA. Plausible models that explain how RNA molecules could have been synthesized from precursor compounds in prebiotic settings were first proposed decades ago, and have since received substantial experimental support. Moreover, its conformational versatility allows RNA both to store information and to act as a catalyst. These insights have led to the idea of an ‘RNA world’ that preceded the emergence of DNA, which is now well established among specialists. How then were the first DNA subunits synthesized? The generally accepted view is that this process was catalyzed by an enzyme – a comparatively complex biomolecule whose emergence would have required millions of years of evolution.

We identified a much more direct mechanism for the synthesis of DNA subunits from organic compounds that would have been present in a prebiotic environment. The necessary ingredients are water, a mildly alkaline pH and temperatures of between 40 and 70°C. Under such conditions, adequately high reaction rates and product yields are achieved, with high selectivity and correct stereochemistry.

Each of the nucleoside subunits found in DNA is made up of a nitrogen-containing base and a sugar called deoxyribose. Up to now, it was thought that deoxynucleosides could only be synthesized under prebiotic conditions by directly coupling these two – preformed – components together. But no plausible non-enzymatic mechanism for such a step had ever been proposed. The essential feature of the new pathway, as Trapp explains, is that the sugar is not linked to the base in a single step. Instead, it is built up on the preformed base by a short sequence of reaction steps involving simple organic molecules such as acetaldehyde and glyceraldehyde. In addition, the LMU researchers have identified a second family of possible precursors of DNA in which the deoxyribose moiety is replaced by a different sugar.

These results suggest that the earliest DNA molecules could have appeared in parallel with RNA – some 4 billion years ago. This would mean that DNA molecules emerged around 400 million years earlier than previously thought.

Link to the publication J. S. Teichert, F. M. Kruse, O. Trapp, Angew. Chem. Int. Ed. 2019, 58, 9944-9947