The behavior and/or internal activities of a microorganism can be simulated using a model of the microorganism. Such simulations can be used to determine the efficacy of treatments, disinfectants, antibiotics, chemotherapies, or other methods of interacting with the microorganism, or to provide some other information about the microorganism. Systems and methods are provided herein for fitting, refining, or otherwise improving such models in an automated fashion. Such systems and methods include performing whole-cell experiments to determine a correspondence between the predictions of such models and the actual behavior of samples of the microorganism. Such systems and methods also include, based on such determined correspondences, directly assessing determined discrete sets of properties of the microorganism and/or of constituents of the microorganism and updating parameters of the model corresponding to the properties of the discrete set such that the overall accuracy of the model is improved.