A fine balance between weak molecule-molecule interactions and usually only weakly laterally varying molecule-substrate interactions governs the physical structure of organic-inorganic and organic-organic heteroepitaxial thin films. Therefore, it is important to investigate the energetics of realistically large overlayer domains. So far, Potential calculations for large domains of organic overlayers on crystalline substrates were computationally demanding due to the vast number of atoms to be considered. Here, we present a technique which for the first time enables the calculation of both the molecule-substrate interaction potential and the molecule-molecule interaction potential for large molecular domains (up to several thousands of rather large molecules) by utilizing potential energy grid files. This technique does not only allow the investigation of the substrate influence but also full Monte-Carlo based structural optimizations, if applied to 2D crystalline overlayers. Furthermore, it provides an estimate for the energetic gain combined with the differently aligned overlayer domains. In several examples we will discuss the usefulness of this method. As a general result, we will provide evidence that energetically favorable lattice structures in OMBE systems are not restricted to commensurate unit cells or coincident super cells.