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Quantitative modelling and analysis of biochemical networks is challenging because of the inherent complexities and nonlinearities of the system and the limited availability of parameter values. Even if a mathematical model of the network can be developed, the lack of large-scale good-quality data makes accurate estimation of a large number of parameters impossible. Hence, coarse-grained models (CGMs) consisting of essential biochemical mechanisms are more suitable for computational analysis and for studying important systemic functions. The central question in constructing a CGM is which mechanisms should be deemed dasiaessentialdasia and which can be ignored. Also, how should parameter values be defined when data are sparse? A mixed-integer nonlinear-programming (MINLP) based optimisation approach to coarse-graining is presented. Starting with a detailed biochemical model with associated computational details (reaction network and mathematical description) and data on the biochemical system, the structure and the parameters of a CGM can be determined simultaneously. In this optimisation problem, the authors use a genetic algorithm to simultaneously identify parameter values and remove unimportant reactions. The methodology is exemplified by developing two CGMs for the GTPase-cycle module of M1 muscarinic acetylcholine receptor, Gq, and regulator of G protein signalling 4 [RGS4, a GTPase-activating protein (GAP)] starting from a detailed model of 48 reactions. Both the CGMs have only 17 reactions, fit experimental data well and predict, as does the detailed model, four limiting signalling regimes (LSRs) corresponding to the extremes of receptor and GAP concentration. The authors demonstrate that coarse-graining, in addition to resulting in a reduced-order model, also provides insights into the mechanisms in the network. The best CGM obtained for the GTPase cycle also contains an unconventional mechanism and its predictions explain an old problem in pharmacology, t- e biphasic (bell-shaped) response to certain drugs. The MINLP methodology is broadly applicable to larger and complex (dense) biochemical modules.