Text S1: Method Detail – Determining Host Metabolic Limitations on Viral Replication via Integrated Modeling and Experimental Perturbation

The media definitions used for simulations are given in Table S1. The three minimal media are welldefined; the Tryptone media composition is based on the BD Bionutrients Technical Manual. While most metabolite media components are considered exhaustible, some metabolites are present in excess, which is simulated by returning to a preset concentration at every FBA time step. Certain modifications had to be made in the integrated model to account for different media conditions. For example, our experiments were performed at 37◦C, but the original T7 ODEs were produced to model a 30◦C environment. We therefore modified some of the parameters, as listed and explained in Table S5. Equilibrium binding constants were assumed not to change with temperature. Parameters not listed in Table S5 are consistent with previous implementations [1]. Furthermore, the original FBA regulatory rules identified in [2] had never been optimized for growth on rich media, and the model was therefore very limited in its ability to simulate reasonable growth rates. We therefore relaxed several of these rules to allow smooth growth on media containing only amino acid carbon sources in the combination present in our representation of tryptone. A list of relaxed regulatory rules is given in (Table S2). Some of the FBA uptake bounds were determined by fitting dynamic rFBA simulations to experimental measurements in the absence of virus. Experimental data for host growth in the different media are shown, together with fitted exponentials, in Figure S1. The measured growth rates were: tryptone μ = 1.5 hour−1, glucose μ = 0.66 hour−1, succinate μ = 0.45 hour−1, and acetate μ = 0.27 hour−1. Also shown are dynamic regulatory FBA simulations of host growth, the growth rates of which were fit via flux bound changes to the growth rate found by exponential fit. These fits were produced by estimation of key flux bounds, as follows: