In PE, the interaction energy between QM and MM subsystems, denoted as E QM/MM , is composed of several contributions. These include the energy from the permanent electrostatic moments of the particles in the MM region (E QM/MM es ), the polarization contribution (E QM/MM pol ), and contributions from van der Waals interactions, E QM/MM vdW . The latter is typically approximated using pairwise 6-12 Lennard-Jones potentials acting on the nuclei. In such a formalism, there is a lack of Pauli repulsion between the QM and MM regions which often leads to electron density leaking into the environment. This is an unphysical effect known as electron spill-out (ESO). This effect is particularly pronounced with basis sets that include diffusion functions. Although removing these functions may mitigate the ESO, it risks compromising an accurate description of the excited states. An effective solution to ESO involves strategically placing effective core potentials (ECPs) at the positions of the MM atoms, which mimics the Pauli repulsion missing in the PE model. In this study, we have placed ECPs on all atoms belonging to fragments (excluding lipids) that have at least one atom within 6 Å from any atom of RSB. We exclude placing ECPs in the C α atom, i.e. the boundary between the QM and MM subsystems. This is done to prevent spurious interactions with the linking hydrogen atom. Additionally, to further minimize any residual effects of ESO, the hydrogen link atom is described using a STO-3G basis set.