Siddhant Sharma

Hydrogen cyanide (HCN)-derived molecules and polymers feature in several hypotheses on the origin of life. Over half-a-century of investigations into HCN self-reactions have led to many suggestions regarding the structural nature of the products, and an even greater number of proposed polymerization pathways. A comprehensive overview of possible reactions and structures is missing. In this work, we use quantum chemical calculations to map the relative free energy of most HCN-derived molecules and polymers that have been discussed in the literature. Our computed free energies indicate that several previously considered polymerization pathways are not spontaneous and should be discarded from future consideration. Among the most thermodynamically favored products are polyaminoimidazole and adenine.

Results in mice suggest that vitamin D reduces the symptoms of asthma by controlling an immune response that leads to inflammation of the airways.

The formose reaction (FR) autocatalytically converts simple plausibly prebiotic feedstocks into molecules of biological interest, including ribose. Autocatalysis is a hallmark of life, thus various studies have explored the formose reaction with respect to the origins of life. The FR is robust under appropriate conditions, occurring readily at low temperatures from various substrates, and has been implicated in the generation of meteoritic organic compounds. We explored the FR here using a combination of in silico modeling techniques and high resolution mass spectrometry. The models match experimental results well, and point to the FR being much more complex than previously modeled or measured, and help explain the FR’s potential to generate homochirality and primitive compartments, both of which are also hallmarks of life, before the emergence of the complex directed molecular encoding suggested by the RNA World model. These results suggest the FR requires further study with regard to the origins of life, and its importance may lie in the way it enables and coordinates emergent chemistries, rather than the particular products it generates, such as ribose.

Amyloid‐based prions have simple structures, a wide phylogenetic distribution, and a plethora of functions in contemporary organisms, suggesting they may be an ancient phenomenon. However, this hypothesis has yet to be addressed with a systematic, computational, and experimental approach. Here we present a framework to help guide future experimental verification of candidate prions with conserved functions to understand their role in the early stages of evolution and potentially in the origins of life. We identified candidate prions in all high‐quality proteomes available in UniProt computationally, assessed their phylogenomic distributions, and analyzed candidate‐prion functional annotations. Of the 27 980 560 proteins scanned, 228 561 were identified as candidate prions (~0.82%). Among these candidates, there were 84 Gene Ontology (GO) terms conserved across the three domains of life. We found that candidate prions with a possible role in adaptation were particularly well‐represented within this group. We discuss unifying features of candidate prions to elucidate the primeval roles of prions and their associated functions. Candidate prions annotated as transcription factors, DNA binding, and kinases are particularly well suited to generating diverse responses to changes in their environment and could allow for adaptation and population expansion into more diverse environments. We hypothesized that a relationship between these functions and candidate prions could be evolutionarily ancient, even if individual prion domains themselves are not evolutionarily conserved. Candidate prions annotated with these universally occurring functions potentially represent the oldest extant prions on Earth and are therefore excellent experimental targets.

Introduction: Hydrogen Cyanide (HCN) is a ubiquitous and reactive species present in many environments ranging from the interstellar medium to comets, asteroids, and planetary atmospheres. HCN and HCN polymers have a proposed key role in the abiotic origin of life and are suspected to be an essential prebiotic building block for the synthesis of nucleobases, amino acids, and a large variety of polymers (Ruiz-Bermejo et al., 2021). HCN is, for example, generated in large amounts by the atmospheric photochemistry of Saturn’s moon Titan (Molter et al., 2016), where it is expected to play a key role in chemical evolution (Cable et al., 2012). Despite many decades of research, the complex nature of products derived from HCN polymerization experiments remains largely unknown. Thus, HCN and its reactivity are very important for prebiotic chemistry (Sandström & Rahm, 2021). Methodology: Figure 1. An overview of the methodology for computing Gibbs free energy (ΔG°298K) content for the polymeric structures in our study. We describe how quantum chemical calculations and simulations can garner insight into the possible prebiotic synthesis of macromolecules and polymers. Our evaluation covers several molecules and oligomers, most of which have been discussed in the literature, and ranks them based on thermodynamic preference (Figure1). We sidestep the complexities of experimental reaction mixtures by computationally exploring individual candidate prebiotic molecules and polymers in solution. A method for conformational sampling is combined with Density Functional Theory (DFT) to predict the thermodynamic stability of most HCN-based structures considered in the literature. This data is used to construct a thermodynamic map to evaluate the feasibility of various structures and reaction hypotheses. Results: Our enumeration of thermodynamically plausible reaction products and the reaction routes for the abiotic formation of organic macromolecules starting from simple units of HCN offers extensive insights into the chemical and physical limitations of suspected key prebiotic processes. Some structures and reactions suggested in the literature are here proven unviable on thermodynamic grounds. However, most HCN-self reactions are found to be spontaneous. Polyaminoimidazole, and the nucleobase adenine, are computed to be the most thermodynamically favoured products that can form from HCN. The presented thermodynamics of HCN polymerization coupled with predictions of closely competing reaction kinetics have several consequences for interpreting HCN reactivity in various astrochemical environments and may help explain experimental observations of complex reaction mixtures. References Ruiz-Bermejo, M. et al. (2021). Processes, 9(4), 597. Molter, E.M. et al. (2016) Astron J, 152, 42/1-42/ Cable, M.L. et al. (2012) Chem Rev, 112, 1882-1909. Sandström, H. et al. (2021). ACS Earth Space Chem, 5(8), 2152-2159.

Amyloid-based prions have simple structures, a wide phylogenetic distribution, and a plethora of functions in contemporary organisms, suggesting they may be an ancient phenomenon. However, this hypothesis has yet to be addressed with a systematic, computational, and experimental approach. Here we present a framework to help guide future experimental verification of candidate prions with conserved functions in order to understand their role in the early stages of evolution and potentially in the origins of life. We identified candidate prions in all high-quality proteomes available in UniProt computationally, assessed their phylogenomic distributions, and analyzed candidate-prion functional annotations. Of the 27,980,560 proteins scanned, 228,561 were identified as candidate prions (∼0.82%). Among these candidates, there were 84 Gene Ontology (GO) terms conserved across the 3 domains of life. We found that candidate prions with a possible role in adaptation were particularly well-represented within this group. We discuss unifying features of candidate prions to elucidate the primeval roles of prions and their associated functions. Candidate prions annotated as transcription factors, DNA binding, and kinases are particularly well suited to generating diverse responses to changes in their environment and could allow for adaptation and population expansion into more diverse environments. We hypothesized that these functions could be evolutionarily ancient, even if individual prion domains themselves are not evolutionarily conserved. Candidate prions annotated with these universally-occurring functions potentially represent the oldest extant prions on Earth and are therefore excellent experimental targets.

We present an open-source chemoinformatic workflow to generate and analyze complex abiological chemical networks to discover novel compounds and autocatalytic processes. We demonstrate this pipeline's capabilities against a well-studied model system.

Hydrogen cyanide (HCN) is a widely available molecule in planetary and interplanetary environments. It has been observed that the polymerization of HCN can lead to the formation of nucleobases and proteins (Matthews & Minard 2006). Thus, HCN and its reactivity are considered to be very important for prebiotic chemistry. Our evaluation covers several molecules and oligomers, most of which have been discussed in the literature (Ruiz-Bermejo et al., 2021), and ranks them based on thermodynamic preference. In our study, we compute the relative energies of a series of HCN-derived materials relative to HCN in liquid water. We perform an automated search with semi-empirical methods to extract the lowest energy conformers for each compound. Our work relies on density functional theory (DFT) calculations with thermal corrections coupled to an implicit solvation model to better emulate the polymerization environments. These methodologies allow us to discuss the impact of our results at relevant environments such as that of Saturn’s Moon Titan or the early Earth conditions. The most stable HCN-derived material in our set is the nucleobase adenine, computed to lie ~26 kcal mol-1 below HCN in a water solution. Our enumeration of thermodynamically plausible reaction products and the reaction routes for the abiotic formation of organic macromolecules starting from simple units of HCN offers extensive insights into the chemical and the physical limitations of suspected key prebiotic processes (Sandström & Rahm 2021). 1. C. N. Matthews, R. D. Minard, Faraday Discuss. 2006, 133, 393. 2. M. Ruiz-Bermejo, J. L. de la Fuente, C. Pérez-Fernández, E. Mateo-Martí, Processes 2021, 9, 597. 3. H. Sandström, M. Rahm, ACS Earth Space Chem. 2021, 5, 2152–2159.