A B S T R A C T An enhanced scatter search (eSS) with combined opposition-based learning algorithm is proposed to solve large-scale parameter estimation in kinetic models of biochemical systems. The proposed algorithm is an extension of eSS with three important improvements in terms of: reference set (RefSet) formation, RefSet combination, and RefSet intensification. Due to the difficulty in estimating kinetic parameter values in the presence of noise and large number of parameters

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... on), the aforementioned eSS mechanisms have been improved using combination of quasi-opposition and quasi-reflection, which were under the family of opposition-based learning scheme. The proposed algorithm is tested using one set of benchmark function each from large-scale global optimization (LSGO) problem as well as parameter estimation problem. The LSGO problem consists of 11 functions with 1000 dimensions. For parameter estimation, around 116 kinetic parameters in Chinese hamster ovary (CHO) cells and central carbon metabolism of E. coli are estimated. The results revealed that the proposed algorithm is superior to eSS and other competitive algorithms in terms of its efficiency in minimizing objective function value and having faster convergence rate. The proposed algorithm also required lower computational resources, especially number of function evaluations performed and computation time. In addition, the estimated kinetic parameter values obtained from the proposed algorithm produced the best fit to a set of experimental data.