scalable rule-based modelling of allosteric proteins and biochemical networks别构蛋白和生化网络的可扩展的基于规则的建模.pdfVIP

Scalable Rule-Based Modelling of Allosteric Proteins and Biochemical Networks 1,2 3 2 Julien F. Ollivier *, Vahid Shahrezaei , Peter S. Swain * ´ 1 Centre for Nonlinear Dynamics, Department of Physiology, McGill University, Montreal, Quebec, Canada, 2 Centre for Systems Biology at Edinburgh, University of Edinburgh, Edinburgh, United Kingdom, 3 Department of Mathematics, Imperial College London, London, United Kingdom Abstract Much of the complexity of biochemical networks comes from the information-processing abilities of allosteric proteins, be they receptors, ion-channels, signalling molecules or transcription factors. An allosteric protein can be uniquely regulated by each combination of input molecules that it binds. This ‘‘regulatory complexity’’ causes a combinatorial increase in the number of parameters required to fit experimental data as the number of protein interactions increases. It therefore challenges the creation, updating, and re-use of biochemical models. Here, we propose a rule-based modelling framework that exploits the intrinsic modularity of protein structure to address regulatory complexity. Rather than treating proteins as ‘‘black boxes’’, we model their hierarchical structure and, as conformational changes, internal dynamics. By modelling the regulation of allosteric proteins through these conformational changes, we often decrease the number of parameters required to fit data, and so reduce over-fitting and improve the predictive power of a model. Our method is thermodyn