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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. 

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.