Correction: Monte-Carlo Modeling of the Central Carbon Metabolism of Lactococcus lactis: Insights into Metabolic Regulation

Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, mediumand large-scale metabolic networks models. Citation: Murabito E, Verma M, Bekker M, Bellomo D, Westerhoff HV, et al. (2014) Monte-Carlo Modeling of the Central Carbon Metabolism of Lactococcus lactis : Insights into Metabolic Regulation. PLoS ONE 9(9): e106453. doi:10.1371/journal.pone. 0106453 Editor: Ying Xu, University of Georgia, United States of America Received February 10, 2014; Accepted August 7, 2014; Published September 30, 2014 Copyright: 2014 Murabito 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: HVW acknowledges support by the transnational program Systems Biology of MicroOrganisms (SysMO) and ERASysBio program and its funders EPSRC/ BBSRC for the following projects: R111828, MOSES project, ERASysBio, BB/F003528/1, BB/C008219/1, BB/F003544/1, BB/I004696/1, BB/I00470X/1, BB/I017186/1, EP/D508053/1, BB/I017186/1. RS acknowledges funding by the OPVK project "Local Team and International Consortium for Computational Modelling of a Cyanobacterial Cell, Reg. No. CZ.1. 07/2.3. 00/20.0256". As of 1.1. 2013, RS is supported by the framework e:Bio of the BMBF (Förderkennzeichen 0316192). 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. * Email: ettore.murabito@manchester.ac. uk (EM); ralf.steuer@hu-berlin.de (RS)