When Is a Reaction Network a Metabolism? Criteria for Simple Metabolisms That Support Growth and Division of Protocells

With the aim of better understanding the nature of metabolism in the first cells and the relationship between the origin of life and the origin of metabolism, we propose three criteria that a chemical reaction system must satisfy in order to constitute a metabolism that would be capable of sustaining growth and division of a protocell. (1) Biomolecules produced by the reaction system must be maintained at high concentration inside the cell while they remain at low or zero concentration outside. (2) The total solute concentration inside the cell must be higher than outside, so there is a positive osmotic pressure that drives cell growth. (3) The metabolic rate (i.e., the rate of mass throughput) must be higher inside the cell than outside. We give examples of small-molecule reaction systems that satisfy these criteria, and others which do not, firstly considering fixed-volume compartments, and secondly, lipid vesicles that can grow and divide. If the criteria are satisfied, and if a supply of lipid is available outside the cell, then continued growth of membrane surface area occurs alongside the increase in volume of the cell. If the metabolism synthesizes more lipid inside the cell, then the membrane surface area can increase proportionately faster than the cell volume, in which case cell division is possible. The three criteria can be satisfied if the reaction system is bistable, because different concentrations can exist inside and out while the rate constants of all the reactions are the same. If the reaction system is monostable, the criteria can only be satisfied if there is a reason why the rate constants are different inside and out (for example, the decay rates of biomolecules are faster outside, or the formation rates of biomolecules are slower outside). If this difference between inside and outside does not exist, a monostable reaction system cannot sustain cell growth and division. We show that a reaction system for template-directed RNA polymerization can satisfy the requirements for a metabolism, even if the small-molecule reactions that make the single nucleotides do not.