Toward a networked central dogma: protein specificity reshapes molecular encounters across evolution

Since its formulation in 1958, the Central Dogma has provided the organizing framework for molecular biology, describing the informational relationships among DNA, RNA, and protein. Yet, the framework ends at protein synthesis: what proteins do after they are made, how their catalytic specificities determine which molecules actually meet inside the cell, lies beyond its scope. Using a zero-parameter physical model applied to three phylogenetically distant species, we show that physical encounter frequency and metabolic flux are decoupled: raw collision rates predict reaction importance only weakly and show no consistent link to gene essentiality. Enzymatic selectivity bridges this gap through three distinct, species-conserved rescue patterns that persist across more than a billion years of evolution. The cell’s most critical metabolic hubs are, paradoxically, its physically least conspicuous ones— rescued from the collision background by enzymatic precision alone. We term this downstream, measurable layer the Networked Central Dogma: a complement to the classical schema that connects gene expression to the physical organization of cellular chemistry.