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Abstract Water, the most abundant compound on the surface of the Earth and probably in the universe, is the medium of biology, but is much more than that. Water is the most frequent actor in the chemistry of metabolism. Our quantitation here reveals that water accounts for 99.4% of metabolites in Escherichia coli by molar concentration. Between a third and a half of known biochemical reactions involve consumption or production of water. We calculated the chemical flux of water and observed that in the life of a cell, a given water molecule frequently and repeatedly serves as a reaction substrate, intermediate, cofactor, and product. Our results show that as an E. coli cell replicates in the presence of molecular oxygen, an average in vivo water molecule is chemically transformed or is mechanistically involved in catalysis ~ 3.7 times. We conclude that, for biological water, there is no distinction between medium and chemical participant. Chemical transformations of water provide a basis for understanding not only extant biochemistry, but the origins of life. Because the chemistry of water dominates metabolism and also drives biological synthesis and degradation, it seems likely that metabolism co-evolved with biopolymers, which helps to reconcile polymer-first versus metabolism-first theories for the origins of life. 

Abstract The helical structures of DNA and RNA were originally revealed by experimental data. Likewise, the development of programs for modeling these natural polymers was guided by known structures. These nucleic acid polymers represent only two members of a potentially vast class of polymers with similar structural features, but that differ from DNA and RNA in the backbone or nucleobases. Xeno nucleic acids (XNAs) incorporate alternative backbones that affect the conformational, chemical, and thermodynamic properties of XNAs. Given the vast chemical space of possible XNAs, computational modeling of alternative nucleic acids can accelerate the search for plausible nucleic acid analogs and guide their rational design. Additionally, a tool for the modeling of nucleic acids could help reveal what nucleic acid polymers may have existed before RNA in the early evolution of life. To aid the development of novel XNA polymers and the search for possible pre-RNA candidates, this article presents the proto-Nucleic Acid Builder (https://github.com/GT-NucleicAcids/pnab), an open-source program for modeling nucleic acid analogs with alternative backbones and nucleobases. The torsion-driven conformation search procedure implemented here predicts structures with good accuracy compared to experimental structures, and correctly demonstrates the correlation between the helical structure and the backbone conformation in DNA and RNA. 

The prebiotic origins of ribose, nucleosides, and eventually RNA are enduring questions whose answers are central to the RNA world hypothesis. The abiotic synthesis of sugars was first demonstrated over a century ago, but no known prebiotic reaction produces ribose (an aldose sugar) selectively and in good yield. In contrast, ribulose, and fructose (ketose sugars) and other monosaccharides are formed in high yield by several robust abiotic reactions. It is reported here that ketose sugars ‐ both ketopentoses and ketohexoes ‐ serve as precursors for the formation of ribosides and other aldosides, as demonstrated by glycoside‐forming reactions involving barbituric acid, a plausibly prebiotic nucleobase. Moreover, a one‐pot reaction of glyceraldehyde and barbituric acid was discovered which under mild conditions, and without special minerals or other catalysts, results in the formation of glycosides. These results reveal that an exclusive or high‐yielding generation of free ribose was not required for its incorporation into processes that provided the foundations for life.

 

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. Here we show that cationic proto-peptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct interactions with RNA resulting in mutual stabilization. Cationic proto-peptides significantly increase the thermal stability of folded RNA structures. In turn, RNA increases the lifetime of a depsipeptide by >30-fold. Proto-peptides containing the proteinaceous amino acids Lys, Arg, or His adjacent to backbone ester bonds generally promote RNA duplex thermal stability to a greater magnitude than do analogous sequences containing non-proteinaceous residues. Our findings support a model in which tightly-intertwined biological dependencies of RNA and protein reflect a long co-evolutionary history that began with rudimentary, mutually-stabilizing interactions at early stages of polypeptide and nucleic acid co-existence.

 

The prebiotic origins of biopolymers and metabolic co‐factors are key questions in Origins of Life studies. In a simple warm‐little‐pond model, using a drying phase to produce a urea‐enriched solution, we present a prebiotic synthetic path for the simultaneous formation of neopterins and tetrahydroneopterins, along with purine nucleosides. We show that, in the presence of ribose and in a formylating environment consisting of urea, ammonium formate, and water (UAFW), the formation of neopterins from pyrimidine precursors is robust, while the simultaneous formation of guanosine requires a significantly higher ribose concentration. Furthermore, these reactions provide a tetrahydropterin–pterin redox pair. This model suggests a prebiotic link in the origin of purine nucleosides and pterin cofactors that provides a possible deep prebiotic temporal connection for the emergence of nucleic acids and metabolic cofactors.

 

Chemical ligation is an important tool for the generation of synthetic DNA structures, which are used for a wide range of applications. Surprisingly, reported chemical ligation yields can range from 30 to 95 % for the same chemical activating agent and comparable DNA structures. We report a systematic study of DNA ligation by using a well‐defined bimolecular test system and a water‐soluble carbodiimide (EDC) as a phosphate‐activating agent. Our results emphasize the interplay between template‐substrate complex stability and the rates of the chemical steps of ligation, with 3′ phosphate substrates providing yields near 100 % after 24 hours for particularly favorable reaction conditions. Ligation rates are also shown to be sensitive to the identity of the base pairs flanking a nick site, with as much as threefold variation. Finally, the observation that DNA substrates are modified by EDC at rates that can be comparable with ligation rates emphasizes the importance of considering side reactions when designing protocols to maximize ligation yields.

 

The cyanuric acid (CA) heterocycle forms supramolecular structures with adenine nucleobases/nucleosides and oligonucleotides, leading to speculation that they can act as forerunners to RNA. Herein, the assembly behavior of RNA containing CA and CA–ribose nucleoside was studied. Contrary to previous reports, CA in RNA and the CA‐ribonucleoside resulted in destabilization of supramolecular assemblies, which led to a reevaluation of the CA–adenine hexameric rosette structure. An unprecedented noncovalent supramolecular helicene structure is proposed to account for the striking difference in behavior, which has implications for novel paradigms for reorganizing the structures of nucleic acids, the synthesis of long helicenes, and pre‐RNA world paradigms. The results caution against extrapolating the self‐assembly behavior of individual heterocycles from the level of monomers to oligomers because the base‐paring properties of (non‐)canonical nucleobases are impacted by the type of oligomeric backbone to which they are attached.