The master molecule that built biology: How water shaped the chemistry of life.

The deep entanglement of biomolecular structure and function with aqueous systems supports the view that water actively sculpted both molecules and processes during the origins of life and continues to constrain evolution today. Nature's rules of biochemistry and biophysics have survived for nearly 4 billion years. The in vivo roles of water, the architectures of biopolymer backbones and side chains, the structure and function of ribose, ATP, the translation system, the genetic code, and certain inorganic cations persist unchanged. Hydrogen bonding and the hydrophobic effect predate life on Earth altogether. Here we examine fundamental forces that established, shaped, and continue to constrain biochemistry and biophysics. The results support a model in which life emerged through water-based selection among diverse molecules and molecular ensembles, with molecular fitness defined by behaviors in and interactions with water. Life is thus composed of molecules that cooperate with, resist, and exploit the unique properties of water. Biological molecules employ chemical strategies that enable selective and controlled persistence in aqueous environments, a phenomenon we classify as recalcitrance. Molecular assembly reduces conformational heterogeneity, constrains dynamics, and sterically excludes reactive agents, including water and hydrolytic enzymes. By this mechanism, lifetimes of folded proteins, structured RNAs, assembled phospholipids, and polysaccharides are mediated by their organizational states.

© 2026 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.