The JKCS3 run script allows communication with quantum chemistry (QC) programs to refine the cluster geometries and energies. Since the number of trial structures obtained from the exploration step can be enormous, the first optimization step should ideally be performed using a computationally affordable method. One of the extended tight-binding (xTB) semi-empirical methods implemented in the XTB program is a robust choice for many systems, though caution is needed for e.g., reactive and radical systems. The PM6 and PM7 57 methods offer a similar functionality. Subsequent single-point energy refinement or geometry re-optimization can be performed using composite electronic methods such as B97-3c 58 and r 2 SCAN-3c. For instance, Engsvang et al. and Wu et al. showed the applicability of these methods to large (up to 30 molecules) sulfuric acid and ammonia clusters.