MLAGO: machine learning-aided global optimization for Michaelis constant of kinetic modeling

Background: Kinetic modeling is a powerful tool for understanding the dynamic behavior of biochemical systems. For kinetic modeling, determination of a number of kinetic parameters, such as the Michaelis constant (K_m), is necessary, and global optimization algorithms have long been used for parameter estimation. However, the conventional global optimization approach has three problems: (i) It is computationally demanding. (ii) It often yields unrealistic parameter values because it simply seeks a better model fitting to experimentally observed behaviors. (iii) It has difficulty in identifying a unique solution because multiple parameter sets can allow a kinetic model to fit experimental data equally well (the non-identifiability problem). Results: To solve these problems, we propose the Machine Learning-Aided Global Optimization (MLAGO) method for K_m estimation of kinetic modeling. First, we use a machine learning-based K_m predictor based only on three factors: EC number, KEGG Compound ID, and Organism ID, then conduct a constrained global optimization-based parameter estimation by using the machine learning-predicted K_m values as the reference values. The machine learning model achieved relatively good prediction scores: RMSE = 0.795 and R² = 0.536, making the subsequent global optimization easy and practical. The MLAGO approach reduced the error between simulation and experimental data while keeping K_m values close to the machine learning-predicted values. As a result, the MLAGO approach successfully estimated K_m values with less computational cost than the conventional method. Moreover, the MLAGO approach uniquely estimated K_m values, which were close to the measured values. Conclusions: MLAGO overcomes the major problems in parameter estimation, accelerates kinetic modeling, and thus ultimately leads to better understanding of complex cellular systems. The web application for our machine learning-based K_m predictor is accessible at https://sites.google.com/view/kazuhiro-maeda/software-tools-web-apps, which helps modelers perform MLAGO on their own parameter estimation tasks.