The Levinthal paradox of the interactome

The central biological question of the 21st century is: how does a viable cell emerge from the bewildering combinatorial complexity of its molecular components? Here, we estimate the combinatorics of self‐assembling the protein constituents of a yeast cell, a number so vast that the functional interactome could only have emerged by iterative hierarchic assembly of its component sub‐assemblies. A protein can undergo both reversible denaturation and hierarchic self‐assembly spontaneously, but a functioning interactome must expend energy to achieve viability. Consequently, it is implausible that a completely “denatured” cell could be reversibly renatured spontaneously, like a protein. Instead, new cells are generated by the division of pre‐existing cells, an unbroken chain of renewal tracking back through contingent conditions and evolving responses to the origin of life on the prebiotic earth. We surmise that this non‐deterministic temporal continuum could not be reconstructed de novo under present conditions.