A remarkable contribution of quantum chemical methods lies in their ability to elucidate reaction pathways and underlying mechanisms with molecular-level resolution. Numerous computational studies have provided valuable insights into plausible routes for the emergence of life, supporting both information-first and metabolism-first hypotheses.

One of the most significant and well-established prebiotic mechanisms for the formation of amino acids is the Strecker synthesis, which involves the reaction of ammonia, hydrogen cyanide, and aldehydes in aqueous solution. In 2021, the complete reaction mechanism for glycine formation via this pathway was elucidated through detailed quantum chemical calculations (Magrino et al., 2021).

Nonetheless, in 2024 a novel computational route for the aqueous synthesis of glycine was elucidated, uncovering new intermediates through an alternative mechanism to the Strecker synthesis. This pathway is consistent with early Earth conditions as well as with observations from meteoritic samples (Huet et al., 2024). This study illustrates how the recently developed avenues of Artificial Intelligence (AI)- and Machine Learning-based methodologies can effectively complement computational quantum chemistry approaches. In particular, the use of these techniques significantly reduced the computational cost, enabled the identification of a previously unexplored reaction pathway, and still allowed for a comprehensive thermodynamic characterization of the process.

Within the genetics-first framework, a central question has been whether aqueous hydrogen cyanide (HCN) could have given rise to the precursors of RNA on the primitive Earth. A computational investigation employing quantum chemical methods capable of predicting novel reaction pathways addressed this issue in detail. The study revealed that water and HCN could indeed serve as fundamental building blocks for the formation of larger and more complex organic molecules, such as precursors of RNA and proteins, under prebiotic conditions of early Earth. Remarkably, these transformations were found to proceed without the involvement of metal catalysts or photochemical activation, indicating that efficient and chemically viable pathways may have existed intrinsically in the early Earth environment (Das et al., 2019; Meisner et al., 2019).

Nevertheless, this does not mean metal catalysts or photochemistry did not have a role in prebiotic chemistry. In fact, the metabolism-first hypothesis relies on geochemical catalysis. It is therefore evident that knowledge about the early geological environments is desirable, in order to understand what species are more feasible to study. The same for photochemistry: we need to comprehend the primitive geological place to ensure a sufficient amount of light, especially because there were some shielded environments (Cantine and Fournier, 2018). Together with the geological era, we have an even more complete picture of the context of the reaction.

Regarding photochemical prebiotic reactions, it is very important to consider them due to high levels of ultraviolet radiation that the primordial Earth was thought to receive (the ozone layer was only formed because of life, as photosynthesis produced oxygen which accumulated in the atmosphere). The production of some key prebiotic intermediates could have been accounted for by photochemistry—amino acids, nucleobases, and consequently, the prebiotic emergence of RNA and DNA (Cantine and Fournier, 2018; Bertram et al., 2022). Even in HCN chemistry, a computational study supports that photon excitation aids the oligomerization of hydrogen cyanide into a current intermediate in the synthesis of nucleic acids building blocks (Boulanger et al., 2013).

Now, dealing with metallic catalysis, there are several examples of metal-catalyzed prebiotic reactions (Belmonte and Mansy, 2016; Kitadai and Maruyama, 2018; Aithal et al., 2023). A recent investigation elucidated how a specific decarboxylation, currently occurring in the biochemistry of all living organisms and enzymatically catalyzed, reacts abiotically in the presence of some divalent cations. In this study, the metals were theoretically considered in coordination with water molecules. The results were counterintuitive: the best metal in the abiotic reaction was not the one selected to act in enzymes (Yañez et al., 2025).

Another interesting theoretical example reported with a metal catalyst is the formose reaction, an accepted prebiotic formation of sugars. It is noteworthy that in the mechanism proposed, the catalyst, Ca(OH)₂, mediates the formation of new carbon-carbon bonds and plays the role of providing an alkaline reaction environment, in agreement with the hypothesis that life could have appeared in alkaline hydrothermal vents (Venturini and González, 2024).

Metals and minerals can also help in the investigations of chirality. On Earth, it is accepted that metal-ions (like Fe²⁺ and Mg²⁺, for example,) could be involved in the synthesis of chiral compounds (Thripati et al., 2023; Aithal et al., 2023; Lee et al., 2022; Cowan and Furnstahl, 2022). Despite the L-amino acids occurring in proteins, free D-amino acids play a physiological role in a minority of organisms. A computational modelling pointed out that a photocatalytic process on the surface of the pyrite mineral (FeS₂), a widespread mineral on Earth’s crust, could generate a prebiotic asymmetry of biological D-amino acids (Li et al., 2024).

Also, the origin of homochirality in biomolecules may have another intriguing source: the weak nuclear force (Cowan and Furnstahl, 2022; Aucar et al., 2024). A work in 2022 rekindled the debate by presenting a robust model that demonstrates the influence of the weak nuclear force in biochemical and primordial reactions. It was contextualized under the RNA-world hypothesis (genetics-first) and considered in the reactions Ca²⁺, Ba²⁺, and Sr²⁺ because of the geological adequacy (which is, in fact, a conciliation between the genetics- and metabolism-first visions) (Cowan and Furnstahl, 2022).

Along with that, a recent study also revisits the possible influence of the weak force in the generation of the biological enantiomeric bias, theoretically investigating this hypothesis (Aucar et al., 2024). It is claimed the weak force effects are so small that it would be hard to detect them experimentally, making them appropriate for computational work. The conclusions pointed out the relations between the weak force and the molecular chirality, and stresses a protocol for further research in this regard.

Until now, the presented investigations were about the endogenous origin of life building blocks. However, exogenous origin is just as important and can be treated by quantum theories as well, being able to describe a very specific characteristic of quantum systems that usually appears in astrochemical reactions: quantum tunneling.

In the interstellar medium (ISM), temperatures are very small, typically occurring around 100 K (or even smaller). As reaction rates become very slow in this condition, it opens up the possibility for reactions to undergo quantum chemical tunneling (Pérez-Villa et al., 2020).

One notable example is the reaction between ammonia and acetaldehyde. At 10 K in interstellar ices, they react to form organic compounds, with a robust sign of the contribution of quantum tunneling. Moreover, when delivered to Earth, these organics can coordinate with metal cations, such as Na⁺, K⁺, Mg²⁺, and Ca²⁺, believed to be present in prebiotic environments (Marks et al., 2023).

These reactions relate to another prominent scientific field, called quantum biology. This area aims to investigate the possibility and influence of quantum effects in biological systems, in a way that these effects are not only relevant for explaining the biochemistry and biophysics, but are also necessary and essential (Alvarez et al., 2024). The tunneling in prebiotic reactions and the possible role of the weak nuclear force driving molecular biochirality exactly fit in this goal, demonstrating the fundamental role of quantum chemistry in the appearance of life. Similarly, a study by Popa et al. (2009) highlights the importance of nuclear spin in the prebiotic chiral asymmetry scenario.

Previously, we examined the role of metals in some endogenous syntheses. However, their role in astrochemical reactions remains to be addressed. There is a pivotal function metals could play in the interstellar medium: the construction of chirality. A computational investigation showed that metals present in the ISM (at 20 K), such as Al and Mg, are able to react in a barrierless way to form ethylene oxide, the first chiral molecule detected in the ISM, providing insights into the elucidation of chirality in the universe (Thripati et al., 2023).

Another computational study connected metals and light-mediated processes to afford the homochirality used by life: UV absorption by magnesium silicate grains in protoplanetary disks and in the ISM can help to explain the enantiomeric excess observed in meteoric organic molecules, in the same configuration that biological systems need (Stelmach et al., 2024). In this paper, computational methods were employed due to experimental challenges inherent in studying such systems (like a complicated optical detection methodology and simulating the astrophysical conditions), depicting how computational chemistry is a supplementary tool to experiments.

Still treating metals, some minerals are observed both on Earth and on meteorites. As amino acids are commonly encountered in meteorites (e.g., the Murchison meteorite) and are, of course, indispensable for living organisms, understanding their interactions with these minerals is relevant. This was experimentally and theoretically investigated, with sorption mechanisms being explored at varying pH values and temperatures, distinguishing physical and chemical interactions between amino acids and minerals (specifically, olivine and montmorillonite), enriching our knowledge of how surfaces play a role in prebiotic chemistry (Colín-Garcia et al., 2024).

Beyond metals and minerals, astrochemistry also has a distinguished report about a key prebiotic molecule, pyruvate and its protonated species, pyruvic acid. This is relevant because pyruvate appears today in the metabolism of every living organism, in the citric acid cycle (Krebs cycle). Along with its endogenous origins, the exogenous origins in interstellar cold molecular clouds are theoretically also proposed, following a barrierless radical-radical recombination (Kleimeier et al., 2020).

As biorelevant molecules carried by astronomical objects are known to survive in the impact on Earth, this represents a plausible route for abiotic synthesis of pyruvic acid, which is accepted as a prebiotic starting material (Kleimeier et al., 2020). Pyruvate can react to produce a sort of biologically relevant species, such as amino acids, sugars, and other metabolic molecules in Krebs cycle (Muchowska et al., 2020).

Another computational proposal for the formation of pyruvic acid is via soft impact of comets entering the primitive Earth’s atmosphere (Dash et al., 2024). Thus, in this case, the molecule would not be merely delivered, but would have been formed with the aid of the cometary ices entering the planet.

One more meaningful way of employing computational quantum methods is isotopic analysis. Since organics are found in meteorites, the analysis of isotopic composition allows the access to temperature and pathway of formation of the molecules, tracing back the history of our early solar system (Bhattacharjee and Eiler, 2024; Cooper et al., 2011). This understanding is helpful to propose new kinds of astrochemical reactions, shedding light on other molecules potentially delivered to Earth, and participating in the origins of life. Furthermore, tunneling can be indicated by analysis of the kinetic isotopic effect (Marks et al., 2023).

All the previously mentioned examples, in both types of life building blocks origins (endogenous and exogenous), depict how simple molecules and species can react to create molecular complexity (bottom-up approach), ending up in molecules that can support life. This perfectly illustrates what chemical evolution means and demonstrates how life is a product of planetary, astrophysical, and astrochemical conditions.

Computational quantum tools are also valuable for investigating biosignatures. Prebiotic chemistry is a branch of astrobiology; after all, if we understand how life began here, it helps us to pursue life on other planets and moons looking for similar processes (Phillips, 2010). For example, Strecker synthesis is hypothesized to have occurred not only on Earth but on other planets and astronomical bodies as well (Chimiak et al., 2022; Burton et al., 2012; Fresneau et al., 2015). In this search, we aim to find molecules that unequivocally compose life, distinguishing abiotic from biotic processes; these are known as biosignatures. Because computational chemistry provides detailed reaction pathways, this search can be extended, not only with new reactions, but also with new reaction intermediates. Isotopic composition analysis further aids this distinction (Chimiak et al., 2022; Da Pieve, 2019). Isotopic fractionation is also mentioned as a relevant outcome to understand the role of spin chemistry in prebiotic chirality (Popa et al., 2009).

Electronic structure methods are capable of presenting physicochemical properties that could be helpful in this search for biosignatures as well. For instance, a computational study examined some of these properties (in gas and condensed phases) of isoleucine enantiomers and diastereomers found in enantiomeric excess in meteorites. The ability to form hydrogen bonds (a type of non-covalent interaction required for life) and chirality (among many other aspects) are proposed to characterize biomolecular complexity, identifying universal features of life as we know it (Da Pieve, 2019).

Additionally, quantum chemistry can predict molecular spectra, for instance, the infrared spectra. With computational quantum calculations, 958 species containing the atom phosphorus–potentially detectable in planetary atmospheres and even serving as biosignatures–were catalogued regarding their infrared spectra, producing a database and filling this experimental gap (Zapata Trujillo et al., 2021).

It is worth noting that, not surprisingly, the mentioned studies share a common computational method: Density Functional Theory (DFT). This theory enables the investigation of diverse chemical systems owing to its good accuracy at a substantially reduced computational cost compared to other quantum-chemical approaches. Furthermore, DFT provides valuable insights into reaction mechanisms by predicting electronic structures, energy barriers, and molecular properties. Beyond these general advantages, DFT has also become a central tool in astrobiology, particularly in research addressing prebiotic chemistry and the origin of life. Its ability to describe complex reactive pathways under extreme or unconventional environments–such as those found in interstellar icy grains, hydrothermal systems, or primitive planetary atmospheres–allows researchers to probe how simple molecules could evolve toward biochemical relevance.

Importantly, although wavefunction-based methods such as configuration interaction (CI) or coupled-cluster calculations offer superior accuracy for many electronic-structure problems, they are often unsuitable for extensive mechanistic exploration in this context. The large number of structures, intermediates, and transition states required to map prebiotic reaction networks would lead to computational times and resource usage that are prohibitive with these high-level correlated methods. Consequently, DFT represents a pragmatic balance between accuracy and feasibility, enabling the systematic investigation of reaction pathways that would otherwise be inaccessible. Hence, the versatility of DFT and its balance between accuracy and efficiency (Sandford et al., 2020) make it the method of choice for exploring complex chemical processes relevant to prebiotic chemistry and the origins of life.

An alternative and widely adopted strategy in computational chemistry is to perform single-point energy calculations using more sophisticated and computationally demanding electronic structure methods, while retaining molecular geometries optimized at the DFT level. In this approach, geometry optimizations and thermodynamic corrections are obtained with a lower-cost method, whereas the electronic energy is refined using a higher-level, more strongly correlated method, as exemplified by the study of Thripati et al. (2023).

This methodology is based on the observation that molecular geometries are generally less sensitive to the level of theory than absolute electronic energies. As a result, the combination of DFT-optimized structures and vibrational contributions with single-point energies computed at a higher level of theory yields more reliable and physically meaningful energetic estimates, while maintaining a substantially reduced computational cost relative to a full optimization at the high-level method.

Moreover, given the wide range of available DFT methodologies (exchange–correlation functionals), it is common practice to perform a preliminary benchmarking study in which selected functionals are systematically assessed and compared against single-point coupled-cluster energies, or suitable coupled-cluster approximations. This procedure enables the identification of the functional that best reproduces the chosen high-level reference. A representative application of this strategy is provided by Bancone et al. (2025), who employed such a benchmarking protocol to investigate the prebiotic dimerization of HCN catalyzed by magnesium silicate (Mg₂SiO₄), a mineral relevant to astronomical environments such as asteroids.

Building on these hybrid approaches and resuming AI-based methodologies, neural-network potentials (NNPs) trained on DFT data and density functional methods have opened the possibility of performing ab initio molecular dynamics at a computational cost comparable to classical force-field simulations (classical molecular dynamics). By learning the underlying quantum-mechanical potential-energy surface directly from high-level electronic-structure data, NNPs circumvent the need to solve the Schrödinger equation at every simulation timestep. As a result, they render feasible exploration of reaction dynamics, free-energy landscapes, and complex chemical transformations relevant to prebiotic chemistry on timescales and system sizes that would be unattainable with conventional ab initio molecular dynamics (Benayad et al., 2024; Tiwary, 2024). This integration of artificial intelligence with quantum chemistry represents a promising frontier for advancing our mechanistic understanding of the chemical origins of life.