ABSTRACT We present here the first of a series of papers aimed at better understanding the evolution and properties of giant molecular clouds (GMCs) in a galactic context. We perform high-resolution, three-dimensional arepo simulations of an interacting galaxy inspired by the well-observed M51 galaxy. Our fiducial simulations include a non-equilibrium, time-dependent, chemical network that follows the evolution of atomic and molecular hydrogen as well as carbon and oxygen self-consistently. Our calculations also treat gas self-gravity and subsequent star formation (described by sink particles), and coupled supernova feedback. In the densest parts of the simulated interstellar medium (ISM), we reach sub-parsec resolution, granting us the ability to resolve individual GMCs and their formation and destruction self-consistently throughout the galaxy. In this initial work, we focus on the general properties of the ISM with a particular focus on the cold star-forming gas. We discuss the role of the interaction with the companion galaxy in generating cold molecular gas and controlling stellar birth. We find that while the interaction drives large-scale gas flows and induces spiral arms in the galaxy, it is of secondary importance in determining gas fractions in the different ISM phases and the overall star formation rate. The behaviour of the gas on small GMC scales instead is mostly controlled by the self-regulating property of the ISM driven by coupled feedback.