The infrared spectroscopy of molecules, complexes, and molecular aggregates dissolved in superfluid helium clusters, commonly called HElium NanoDroplet Isolation (HENDI) spectroscopy, is an established, powerful experimental technique for extracting high resolution ro-vibrational spectra at ultra-low temperatures. Realistic quantum simulations of such systems, in particular in cases where the solute is undergoing a chemical reaction, require accurate solute–helium potentials which are also simple enough to be efficiently evaluated over the vast number of steps required in typical Monte Carlo or molecular dynamics sampling. This precludes using global potential energy surfaces as often parameterized for small complexes in the realm of high-resolution spectroscopic investigations that, in view of the computational effort imposed, are focused on the intermolecular interaction of rigid molecules with helium. Simple Lennard-Jones-like pair potentials, on the other hand, fall short in providing the required flexibility and accuracy in order to account for chemical reactions of the solute molecule. Here, a general scheme of constructing sufficiently accurate site–site potentials for use in typical quantum simulations is presented. This scheme employs atom-based grids, accounts for local and global minima, and is applied to the special case of a HCl(H2O)4 cluster solvated by helium. As a first step, accurate interaction energies of a helium atom with a set of representative configurations sampled from a trajectory following the dissociation of the HCl(H2O)4 cluster were computed using an efficient combination of density functional theory and symmetry-adapted perturbation theory, i.e. the DFT-SAPT approach. For each of the sampled cluster configurations, a helium atom was placed at several hundred positions distributed in space, leading to an overall number of about 400 000 such quantum chemical calculations. The resulting total interaction energies, decomposed into several energetic contributions, served to fit a site–site potential, where the sites are located at the atomic positions and, additionally, pseudo-sites are distributed along the lines joining pairs of atom sites within the molecular cluster. This approach ensures that this solute–helium potential is able to describe both undissociated molecular and dissociated (zwitter-) ionic configurations, as well as the interconnecting reaction pathway without re-adjusting partial charges or other parameters depending on the particular configuration. Test calculations of the larger HCl(H2O)5 cluster interacting with helium demonstrate the transferability of the derived site–site potential. This specific potential can be readily used in quantum simulations of such HCl/water clusters in bulk helium or helium nanodroplets, whereas the underlying construction procedure can be generalized to other molecular solutes in other atomic solvents such as those encountered in rare gas matrix isolation spectroscopy.