Viability Conditions for a Compartmentalized Protometabolic System: A Semi-Empirical Approach Gabriel Piedrafita 1 , Kepa Ruiz-Mirazo 2,3 , Pierre-Alain Monnard 4 , Athel Cornish-Bowden 5 , Francisco Montero 1 * 1 Departamento de Bioquı ´mica y Biologı ´a Molecular I, Universidad Complutense de Madrid, Madrid, Spain, 2 Departamento de Lo ´ gica y Filosofı ´a de la Ciencia, Universidad del Paı ´s Vasco, Donostia-San Sebastia ´n, Spain, 3 Unidad de Biofı ´sica, Consejo Superior de Investigaciones Cientı ´ficas-Universidad del Paı ´s Vasco, Leioa, Spain, 4 Center for Fundamental Living Technology, University of Southern Denmark, Odense, Denmark, 5 Unite ´ de Bioe ´nerge ´tique et Inge ´nierie des Prote ´ines, Centre National de la Recherche Scientifique, Marseille, France Abstract In this work we attempt to find out the extent to which realistic prebiotic compartments, such as fatty acid vesicles, would constrain the chemical network dynamics that could have sustained a minimal form of metabolism. We combine experimental and simulation results to establish the conditions under which a reaction network with a catalytically closed organization (more specifically, an (M,R)-system) would overcome the potential problem of self-suffocation that arises from the limited accessibility of nutrients to its internal reaction domain. The relationship between the permeability of the membrane, the lifetime of the key catalysts and their efficiency (reaction rate enhancement) turns out to be critical. In particular, we show how permeability values constrain the characteristic time scale of the bounded protometabolic processes. From this concrete and illustrative example we finally extend the discussion to a wider evolutionary context. Citation: Piedrafita G, Ruiz-Mirazo K, Monnard P-A, Cornish-Bowden A, Montero F (2012) Viability Conditions for a Compartmentalized Protometabolic System: A Semi-Empirical Approach. PLoS ONE 7(6): e39480. doi:10.1371/journal.pone.0039480 Editor: Chrisantha Thomas Fernando, Queen Mary, University of London, United Kingdom Received April 23, 2012; Accepted May 24, 2012; Published June 27, 2012 Copyright: ß 2012 Piedrafita et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was partially supported by the research projects BFU2009-12895-C02-02 and FFI2011-25665 (Ministerio de Economı ´a y Competitividad, Spain). KRM also acknowledges support by grant IT 505-10 (Gobierno Vasco, Spain). PAM acknowledges support by the Danish National Research Foundation and by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 249032. GP holds a FPU PhD scholarship (Ministerio de Educacio ´ n, Cultura y Deporte, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: framonte@quim.ucm.es Introduction By means of a complex set of interconnected enzymes, living systems have mastered the coupling and kinetic control of chemical reactions leading to robust forms of cyclic self- production, generally conceived as metabolisms. Biochemistry, however, takes place within compartments. All known metabo- lisms are vectorial [1]: they involve gradients, processes occurring in compartmentalized space, diffusion and transport of compounds across diverse boundaries, all of these being deeply entangled with enzyme-regulated chemical pathways. The complementary rela- tionship established between a network of reaction processes and its physical-topological border (most distinctively, the cytoplasmic membrane) has often been highlighted as a central aspect of biological organization, and even considered as the defining feature of life [2,3]. However, despite the claims of the ‘‘compartment-first’’ school of thought in the origins of life research field [4–9] (see also [10]), there have been few empirical or theoretical studies of the actual conditions for viability of that kind of system (see Note 1 in Text S1), i.e. about the mutual physical-chemical constraints that a minimal cyclic reaction network (a protometabolism) and a boundary (e.g. a prebiotic lipid vesicle) impose on each other. Until recently, self-assembling compartments (in particular, topologically closed lipid bilayers, or vesicles) have been regarded as a challenge for the development of any complex chemistry, due to the barrier to the free diffusion of solutes they represent and the corresponding reduction of the molecular precursor accessibility to the inner aqueous core of the system. Therefore, some authors have shown preference for a scheme of prebiotic transitions in which (bio-)chemistry develops without lipid compartments [11– 13] or, at most, in their vicinity [14,15]. Recent experimental work on protocell systems with membranes made of mixtures of fatty acids and other prebiotically plausible amphiphiles [16,17] has shown, however, that vesicles do not necessarily constitute such impermeable barriers [18], particularly for non-ionic and low- molecular-weight compounds. From these new pieces of evidence, an alternative co-evolutionary scenario can be envisioned in which reaction networks would very early be hosted within protocell compartments, becoming increasingly both interdependent and complex thereafter. The role of lipid phases and compartments that likely preceded bio-membranes must have gone beyond their primary anti-dilution effects of preventing the irreversible loss of soluble, non-abundant–but often essential–organic compounds. For example, lipid bilayer and multilayer structures have been reported to assist polymerization of both nucleic acids and peptides in various experimental conditions [19–23], or to harbor light energy transduction mechanisms [24]. In addition, encap- sulating a reaction network (in particular, a network comprising populations of replicating molecules) within a vesicle with potential, itself, for reproduction (as a whole system) has often been underlined as a key evolutionary step towards living PLoS ONE | www.plosone.org 1 June 2012 | Volume 7 | Issue 6 | e39480