The physical structure of organic–inorganic heteroepitaxial thin films is usually governed by a fine balance between weak molecule–molecule interactions and a small lateral variation of the molecule–substrate interaction potential. In order to investigate the energetics of such a layer system, one has to consider large molecular domains [Mannsfeld and Fritz, Phys. Rev. B 69, 75416 (2004)]. So far, layer potential calculations for large domains of organic thin films on crystalline substrates were difficult to perform concerning the computational effort which stems from the huge number of atoms which have to be included. Here, we present a technique which enables the calculation of the molecule–substrate interactions for large molecular domains by utilizing potential energy grid files. As an application example, we discuss the growth of titanylphthalocyanine (TiOPc) on Au(111). TiOPc is found to grow homogeneously in extended domains on top of the alternating domains of the Au(111) surface reconstruction, locally exhibiting a point-on-line coincident epitaxy with the substrate lattice. Here, we demonstrate that the optimal structure and orientation of the TiOPc lattice in such extended overlayer domains can be predicted by potential optimization calculations using the technique described herein.