An effective method to systematically integrate transcriptional regulatory networks and metabolic networks. This allows for the formulation of linear optimization problems that search for metabolic and/or regulatory perturbations that couple biomass and biochemical production, thus proposing adaptive evolutionary strain designs. OptORF is a bi-level optimization problem which identifies the optimal metabolic and regulatory gene deletions as well as gene overexpressions that maximize biochemical production at the maximum cellular growth under transcriptional regulatory constraints. The inner problem of OptORF, which is a linear programming (LP) problem, maximizes growth under the given gene deletions and regulatory states that are determined by the constraints of the outer problem. OptORF is formulated as a single level mixed integer linear program (MILP) by replacing the inner maximization problem with its optimality conditions as constraints.